虾青素的晶型 Astaxanthin crystal form

[0001] 本发明涉及包含虾青素的晶型以及相关的加工、组合物和方法。 [0001] The present invention relates to a crystalline form and related processing, compositions and methods comprising astaxanthin.

[0002] 输送一种着色剂例如具有良好口服生物利用度的虾青素用于改善鲑鱼中等离子体的摄入和肉质的沉积，是鱼饲料生产者和鱼类养殖者特别关心的。 [0002] A coloring agent such as transporting shrimp with good oral bioavailability of astaxanthin for improving plasma deposition salmon intake and meat, fish feed producers and fish farmers of particular concern. 由于在生理学环境中较差的溶解性，采用鱼饲料粒以及其它营养剂型中的虾青素晶体进行给药，不能对所述着色剂产生充分的口服吸收。 Due to the poor solubility in physiologically environment, using fish feed tablets and other nutritional dosage forms administered astaxanthin crystal, can not produce a sufficient oral absorption of the colorant. 为了使着色剂更具生物利用度，已经开发出了几种用于制备颗粒虾青素组合物的方法，所述颗粒虾青素组合物被分散在水中从而制备成饲料粒。 In order to make the toner more bioavailability, several methods have been developed for preparing particulate astaxanthin compositions, the particles astaxanthin composition is dispersed in water to prepare a feed pellets. 所述分散组合物是通过将结晶虾青素在高压和高温下溶解在溶剂（us 6，863，914和US6，406，735)或油（US 5，364，563)中，紧接着将该有机溶液分散在含水的水状胶体中而制备。 The dispersion composition is prepared by crystallization of astaxanthin at high pressure and high temperature in a solvent (us 6,863,914 and US6,406,735) or oil (US 5,364,563), and followed by the The organic solution was dispersed in the aqueous hydrocolloid prepared. 可替代地，将类胡萝卜素融化在含水的赋形剂基质中并在压力下不使用溶剂或油而进行乳化（US6，093，348)。 Alternatively, the melted carotenoid in an aqueous vehicle and a matrix and emulsified (US6,093,348) without using solvent or oil under pressure. 所有的方法都需要进一步的处理从而由水分散体制备粉末制剂。 All methods require further treatment to prepare a water dispersible powder formulation system. 没有一个公开物使用它们通过X-射线衍射和拉曼光谱公开的晶体结构描述虾青素结晶的类型。 No one was using the crystal structure are disclosed publicly through X- ray diffraction and Raman spectra of the type described astaxanthin crystals. 尽管制备虾青素组合物需要复杂的条件，但是还有一些人努力致力于使所述方法更具生产友好性。 Although the preparation of astaxanthin compositions require complicated conditions, but there are people working hard to make the process more productive friendly. 减少能量和溶剂消耗的一个途径是使用具有有利的溶解性、融化或稳定性特征的不同虾青素晶型，从而允许使用更加温和的加工条件。 One way to reduce energy consumption and the use of solvents with favorable solubility, melting or stability characteristics of different astaxanthin crystal form, allowing the use of milder processing conditions. 令人惊奇的是，公开物对虾青素的具体晶型和它们用于制备虾青素组合物的潜在效用都特别沉默。 Surprisingly, the disclosure of specific astaxanthin crystal forms and their preparation for the potential utility of astaxanthin compositions are particularly silent. 不同的晶型可以影响体内的溶解速率，并且允许油性给药媒介中更高的（过饱和的）类胡萝卜素浓度，这样可以提供更高的口服吸收和生物利用度。 Different polymorphs can affect the rate of dissolution of the body and allows higher oil dosing medium (over saturated) carotenoid concentrations, which can offer higher oral absorption and bioavailability.

[0003] US 6，827，941描述了虾青素的无定形集合，其是由丙酮中稀释的虾青素溶液（50毫克/升）通过用7/3(v/v)的水/丙酮进行20次稀释而制备的。 [0003] US 6,827,941 describes an amorphous collection of astaxanthin, astaxanthin which is diluted by the acetone solution (50 mg / l) by 7/3 (v / v) water / acetone 20 times diluted prepared. 它没有涉及具体晶型的形成。 It does not relate to specific crystal formation. US 5，654，488描述了在反应混合物中使用Wittig方法合成和结晶反式-虾青素，但是没有指出晶体的结构或者所获得的结构。 US 5,654,488 describes a method for the synthesis and crystallization using Wittig reaction mixture trans - astaxanthin, but does not indicate the crystal structure or structures obtained.

[0004] 本发明涉及新的以前未公开晶型的混合物以及制备所述晶型的方法，所述混合物包含这里被命名为晶型I和晶型II的虾青素。 [0004] The present invention relates to a novel crystalline form was not disclosed, and the preparation of the crystalline form of the past, where the mixture contains named polymorph I and Phase II of astaxanthin. 此外，本发明描述了晶型I和晶型II及其混合物，所述混合物包含指定量的全-反式-虾青素和不同量的（其它）类胡萝卜素(carotenoidal)化合物。 Furthermore, the present invention describes a polymorph I and Phase II, and mixtures thereof, the mixture contains a specified amount of whole - trans - astaxanthin and varying amounts of (other) carotenoids (carotenoidal) compound. 其进一步覆盖了包含晶型I或晶型II或其混合物的给药形式，以及溶解或悬浮在油或有机溶剂中的晶型I或晶型II或其混合物的用途。 Further covers administration forms containing crystalline polymorph I or II or mixtures thereof, as well as dissolved or suspended in an organic solvent, use an oil or a crystalline form I or form II or mixtures thereof. 该溶液或分散体可以用来制备包含亲水或亲油分散剂载体中的虾青素的固体组合物，或者可以用来制备虾青素的物理形式。 The solution or dispersion can be used to prepare contain hydrophilic or lipophilic dispersant carrier astaxanthin solid composition, or can be used to the physical form of the preparation of astaxanthin.

[0005] 在本发明中使用了如下定义： [0005] the following definitions in the present invention:

[0006] “虾青素”包含全-反式-虾青素（3，3'-二羟基-β，β_胡萝卜素_4，4'-二酮）以及不超过25%重量的其它类胡萝卜素化合物（包括虾青素的顺式异构体）。 [0006] "astaxanthin" consists of all - trans - astaxanthin (3,3'-dihydroxy -β, β_ carotene _4,4'- dione) and not more than 25% by weight of other classes carotene compounds (including astaxanthin cis isomer).

[0007] “类胡萝卜素（carotenoidal)化合物”包括虾青素代谢物、合成或天然的虾青素衍生物例如醚化的或酯化的、氧化或氢化产物以及顺式异构体。 [0007] "carotenoid (carotenoidal) compound" includes astaxanthin metabolites, synthetic or natural astaxanthin derivatives such as etherified or esterified, oxidation or hydrogenated product and cis isomers. 该术语包括在虾青素合成和结晶期间或者在虾青素从天然来源提取加工期间获得的副产物。 The term includes byproducts during synthesis and crystallization of astaxanthin or during the extraction process of astaxanthin from natural sources. 与类胡萝卜素化合物相关的一般虾青素是，例如9-顺式-虾青素、13-顺式-虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛（全-反式-3-羟基-4-氧代-12' -脱辅-β -胡萝卜素-12' -醛，其CAS号为72523-68-3)。 And carotenoid compounds generally related astaxanthin, for example, 9-cis - astaxanthin, 13-cis-- astaxanthin, 15-cis - astaxanthin, astaxanthin, semi - astaxanthin and C-25 aldehyde (all - trans-3-hydroxy-4-oxo -12 '- apo -β - carotene -12' - aldehyde, the CAS No. 72523-68-3). 该术语明确地排除了全-反式-虾青素。 The term specifically excludes full - trans - astaxanthin. 该术语覆盖了US-FDA对虾青素的规范中的“除虾青素以外的所有类胡萝卜素”的条件，其被描述在21 CFR 73.35中。 The term covers the US-FDA astaxanthin of specification "In addition astaxanthin carotenoid all" conditions, which are described in 21 CFR 73.35 in.

[0008] “摩尔表示晶型相对于所含类胡萝卜素总摩尔的纯度，所含类胡萝卜素的总摩尔是全-反式-虾青素和类胡萝卜素化合物的总和。 [0009] 与以图形方式提供的X-射线粉末衍射或拉曼光谱“基本上一致”，即任意谱图都显示相同的峰和最小值顺序，显示在相同波数（拉曼）以及Θ和d晶格间隔位置（X-射线）处，在±5%的标准偏差范围内，所述峰和最小值的强度的相同比值与分别示于图I和图2中的虾青素晶型I的特征X-射线和拉曼光谱或者分别示于图3和图4中的晶型II的X-射线和拉曼光谱一致。 [0008] "Moore said polymorph with respect to the total moles of carotenoid contained in purity, the total molar carotenoid contained in the whole - trans - the sum of astaxanthin and carotenoid compounds [0009] and to X- ray powder diffraction provide graphical or Raman spectroscopy "substantially identical", i.e. arbitrary spectra show the same sequence of peaks and minima, showing the same wave number (Raman) and the lattice spacing d and Θ positions ( X- rays) at within ± 5% of the standard deviation, the same as the ratio of the peak and the minimum intensity and are shown in Figures I and 2, astaxanthin form I characterized by X- ray and Raman spectroscopy or are shown in Figures 3 and 4 in crystalline form II of X- ray and Raman spectra were consistent.

[0010] “约”是指在制备晶型I或晶型II或其混合物的方案中，或者在所述晶型中，在类胡萝卜素化合物的摩尔％界限两边具有20%的标准偏差。 [0010] "about" refers to the preparation of Form I or Form II program, or mixtures thereof, or in the crystal, the mole% threshold on both sides of the carotenoid compound with 20% standard deviation.

[0011] “亲脂性分散剂”是在室温下水溶性低于或等于5毫克/毫升的固体物质，其具有将虾青素分子或胶态分散体或集合包埋入固体组合物中的特性。 [0011] "lipophilic dispersing agent" is a water-soluble less than or equal to 5 mg / ml of the solid material at room temperature, which has the astaxanthin molecule or a colloidal dispersion or set embedded in a solid composition characteristics.

[0012] “亲水性分散剂”是在室温下水溶性高于或等于5毫克/毫升的固体物质，其具有充当润湿剂从而在水相中提高虾青素悬浮的特性。 [0012] "Hydrophilic dispersing agent" is a water-soluble than or equal to 5 mg / mL of solids at room temperature, thereby having a function as a wetting agent in the aqueous phase improved astaxanthin suspension characteristics. 该定义还指油/水乳化剂、聚合物和水状胶体。 This definition also refers to an oil / water emulsifiers, polymers and hydrocolloids.

[0013] “固体组合物”意思是将虾青素分配在固体基质中，所述固体基质是通过将类胡萝卜素和亲脂性或亲水性分散剂一起溶于互溶溶剂或溶剂混合物中，接着除去溶剂或溶剂混 [0013] "solid composition" is meant to astaxanthin distribution in a solid matrix, the solid substrate is produced by carotenoids and lipophilic or hydrophilic dispersing agent is dissolved together miscible solvent or solvent mixture, followed by removal of solvent or solvent mixture

合物而制备的。 Compounds prepared.

[0014] “水溶性溶剂”意思是可以以任何比例与水混合而不出现相分离的溶剂，例如乙醇。 [0014] "aqueous solvent" means that can be mixed in any ratio with water without the occurrence of phase separation of the solvent, such as ethanol.

[0015] “水不溶性溶剂”意思是在不发生相分离的情况下仅能部分地与水混合的溶剂。 [0015] "Water insoluble solvent" means in the case of phase separation does not occur only partially water-miscible solvent.

[0016] “反溶剂”是可与溶剂混溶的结晶液体，全-反式-虾青素和类胡萝卜素化合物都可以溶解在其中，但是在导致具体晶型结晶的温度下具有较低的溶解能力或者几乎不具有溶剂特性（对于虾青素来说）。 [0016] "Anti-solvent" is a solvent miscible with liquid crystalline, all - trans - astaxanthin and carotenoid compounds can be dissolved therein, but with lower temperatures resulting in a specific crystalline polymorph of It has almost no ability to dissolve or solvent properties (for astaxanthin is). 所述定义包括水。 The definition includes water. 根据定义，虾青素在室温或更低温度的反溶剂中具有小于I毫克/毫升的溶解性，例如甲醇。 By definition, astaxanthin has less than I mg / mL solubility in the anti-solvent at room temperature or a lower temperature, such as methanol.

[0017] “生命科学工业”包括食品、饲料、药物、水产养殖、化妆品、营养品、兽医工业。 [0017] "life sciences industries," including food, feed, pharmaceuticals, aquaculture, cosmetics, food, veterinary industries.

[0018] 本发明属于包含天然或合成虾青素的“晶型”和“着色剂组合物”领域。 [0018] The present invention belongs to the "crystal" and "colorant composition" field contains natural or synthetic astaxanthin.

[0019] 本发明描述了以下实施方式： [0019] The present invention describes the following embodiments:

[0020] 一种基本上由虾青素晶型组成的混合物，其包含 [0020] A mixture consisting essentially of astaxanthin crystal composition comprising

[0021] a)晶型I，其特征在于至少如下之一 [0021] a) polymorph I, wherein at least one of the following

[0022] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :8. 0 + 0. K6. 5±0· 05,6. 3±0· 05,6. 1±0· 05,5. 96±0· 05,5. 5 8±0· 05,5. 43±0· 05,4. 87±0· 05、4. 32±0· 05,4. 24±0· 05,4. 21±0· 05,4. 07±0· 05,4. 03±0· 05,3. 58±0· 05,3. 50±0· 05， [0022] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:... 8 0 + 0. K6 5 ± 0 · 05,6 3 ± 0 · 05,6. 1 ± 0 · 05,5. 96 ± 0 · 05,5. 5 8 ± 0 · 05,5. 43 ± 0 · 05,4. 87 ± 0 · 05,4. 32 ± 0 · 05,4. 24 ± 0 · 05,4. 21 ± 0 · 05,4. 07 ± 0 · 05,4. 03 ± 0 · 05,3. 58 ± 0 · 05,3. 50 ± 0 · 05,

[0023] ii)拉曼光谱，其包含在如下位置处的峰：372±2、346±2、333±2、312±2、289±2、234±2、193±2、178±2、133±2、82±201^ ;以及，任选地，至少如下之一 [0023] ii) Raman spectroscopy, which is contained in the peak at the following location: 372 ± 2,346 ± 2,333 ± 2,312 ± 2,289 ± 2,234 ± 2,193 ± 2,178 ± 2, 133 ± 2,82 ± 201 ^; and, optionally, at least one of the following

[0024] iii)显示在212_222°C处发生相转变的DSC扫描；和 [0024] iii) DSC scan showing a phase transition occurs at 212_222 ° C; and

[0025] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为35_45克/升；和[0026] b)晶型II，其特征在于至少如下之一 [0025] iv) at 20 ° C _25 ° C solubility in methylene chloride distribution 35_45 g / l; and [0026] b) crystal type II, type characterized by at least one of the following

[0027] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :7. 2 + 0. K6. 6±0. 05,6. 5±0· 05,5. 48±0· 05,5. 34±0· 05,5. 27+0. 05,4. 49±0· 05,4. 38±0· 05、4. 12±0· 05,3. 89±0· 05,3. 61±0· 05,3. 56±0· 05,3. 34±0· 05,3. 32±0· 05,3. 22±0· 05，和 [0027] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:.... 7 2 + 0. K6 6 ± 0 05,6 5 ± 0 · 05,5. 48 ± 0 · 05,5. 34 ± 0 · 05,5. 27 + 0. 05,4. 49 ± 0 · 05,4. 38 ± 0 · 05,4. 12 ± 0 · 05,3. 89 ± 0 · 05,3. 61 ± 0 · 05,3. 56 ± 0 · 05,3. 34 ± 0 · 05,3. 32 ± 0 · 05,3. 22 ± 0 · 05, and

[0028] ii)拉曼光谱，其包含在如下位置处的峰：376±2、337±2、314±2、304±2、289±2、206±2、180±2、137±2、107±2、93±201^ ;以及，任选地，至少如下之一 [0028] ii) Raman spectroscopy, which is contained in the peak at the following location: 376 ± 2,337 ± 2,314 ± 2,304 ± 2,289 ± 2,206 ± 2,180 ± 2,137 ± 2, 107 ± 2,93 ± 201 ^; and, optionally, at least one of the following

[0029] iii)显示在225_240°C处发生相转变的DSC扫描；和 [0029] iii) DSC scan showing a phase transition occurs at 225_240 ° C; and

[0030] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为10-30克/升。 [0030] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 10 to 30 g / liter.

[0031] 优选的实施方式涉及一种混合物，其基本上由20%到80%重量的被称为晶型I的虾青素结晶形式和80%到20%重量的被称为晶型II的虾青素结晶形式所组成。 [0031] A preferred embodiment relates to a mixture, which is substantially crystalline form pigment astaxanthin crystal Form I is referred to from 20% to 80% by weight and 80% to 20% by weight of polymorph II is known as the astaxanthin crystalline form of the composition.

[0032] 优选的实施方式涉及一种混合物，其基本上由10%到90%重量的被称为晶型I的虾青素结晶形式和90%到10%重量的被称为晶型II的虾青素结晶形式所组成。 [0032] A preferred embodiment relates to a mixture, which is substantially crystalline form of astaxanthin crystal Form I is referred to from 10% to 90% by weight and 90% to 10% by weight of polymorph II is known as the astaxanthin crystalline form of the composition.

[0033] 优选的实施方式涉及一种混合物，其基本上由95%到5%重量的被称为晶型I的虾青素结晶形式和5%到95%重量的被称为晶型II的虾青素结晶形式所组成。 [0033] A preferred embodiment relates to a mixture, which is substantially pigment astaxanthin crystalline form I polymorph is referred to from 95% to 5% by weight and 5% to 95% by weight of polymorph II is known as the astaxanthin crystalline form of the composition.

[0034] 优选的实施方式涉及一种混合物，其基本上由99. 9%到O. I %重量的被称为晶型I的虾青素结晶形式和O. 1%到99. 9%重量的被称为晶型II的虾青素结晶形式所组成。 [0034] The preferred embodiment relates to a mixture consisting essentially of 99.9% to O. I% by weight is referred to as Form I crystalline form of astaxanthin and O. 1% to 99.9% by weight astaxanthin crystal form is called polymorph II of the composition.

[0035] 进一步优选的实施方式涉及一种组合物，其包含特征在于至少如下之一的被称为晶型I的虾青素结晶形式 [0035] A further preferred embodiment relates to a composition comprising at least the following characterized in that the crystalline form of astaxanthin crystal Form I is referred to one of the

[0036] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :8. 0 + 0. K6. 5±0· 05,6. 3±0· 05,6. 1±0· 05,5. 96±0· 05,5. 58±0· 05,5. 43±0· 05,4. 87±0· 05、4. 32±0· 05,4. 24±0· 05,4. 21±0· 05,4. 07±0· 05,4. 03±0· 05,3. 58±0· 05,3. 50±0· 05， [0036] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:... 8 0 + 0. K6 5 ± 0 · 05,6 3 ± 0 · 05,6. 1 ± 0 · 05,5. 96 ± 0 · 05,5. 58 ± 0 · 05,5. 43 ± 0 · 05,4. 87 ± 0 · 05,4. 32 ± 0 · 05,4. 24 ± 0 · 05,4. 21 ± 0 · 05,4. 07 ± 0 · 05,4. 03 ± 0 · 05,3. 58 ± 0 · 05,3. 50 ± 0 · 05,

[0037] ii)拉曼光谱，其包含在如下位置处的峰：372±2、346±2、333±2、312±2、289±2、234±2、193±2、178±2、133±2、82±201^ ;以及，任选地，至少如下之一 [0037] ii) Raman spectroscopy, which is contained in the peak at the following location: 372 ± 2,346 ± 2,333 ± 2,312 ± 2,289 ± 2,234 ± 2,193 ± 2,178 ± 2, 133 ± 2,82 ± 201 ^; and, optionally, at least one of the following

[0038] iii)显示在212_222°C发生相转变的DSC扫描；和 [0038] iii) DSC scan showing a phase transition occurs in 212_222 ° C; and

[0039] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为35-45克/升。 [0039] iv) at 20 ° C _25 ° C solubility in dichloromethane distribution of 35-45 g / l.

[0040] 另一个优选的实施方式涉及一种组合物，其包含特征在于至少如下之一的被称为晶型II的虾青素结晶形式 [0040] Another preferred embodiment relates to a composition comprising at least the following wherein astaxanthin crystal form is called polymorph II is one of the

[0041] i)X_射线衍射图，其包含如下以KTki米表示的晶格面间距d :7. 2 + 0. K6. 6±0. 05,6. 5±0· 05,5. 48±0· 05,5. 34±0· 05,5. 27+0. 05,4. 49±0· 05,4. 38±0· 05、4. 12±0· 05,3. 89±0· 05,3. 61±0· 05,3. 56±0· 05,3. 34±0· 05,3. 32±0· 05,3. 22±0· 05，和 [0041] i) X_-ray diffraction pattern, comprising the following lattice plane spacing d expressed in meters KTki:..... 7 2 + 0. K6 6 ± 0 05,6 5 ± 0 · 05,5 48 ± 0 · 05,5. 34 ± 0 · 05,5. 27 + 0. 05,4. 49 ± 0 · 05,4. 38 ± 0 · 05,4. 12 ± 0 · 05,3. 89 ± 0 · 05,3. 61 ± 0 · 05,3. 56 ± 0 · 05,3. 34 ± 0 · 05,3. 32 ± 0 · 05,3. 22 ± 0 · 05, and

[0042] ii)拉曼光谱，其包含在如下位置处的峰：376±2、337±2、314±2、304±2、289±2、206±2、180±2、137±2、107±2、93±201^ ;以及，任选地，至少如下之一 [0042] ii) Raman spectroscopy, which is contained in the peak at the following location: 376 ± 2,337 ± 2,314 ± 2,304 ± 2,289 ± 2,206 ± 2,180 ± 2,137 ± 2, 107 ± 2,93 ± 201 ^; and, optionally, at least one of the following

[0043] iii)显示在225_240°C处发生相转变的DSC扫描；和 [0043] iii) DSC scan showing a phase transition occurs at 225_240 ° C; and

[0044] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为10-30克/升。 [0044] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 10 to 30 g / liter.

[0045] 本发明另外的内容是一种制备上述组合物的方法，其包括将赋形剂加入到晶型I中，和一种方法，其包括将赋形剂加入到晶型II中。 Method [0045] The present invention further content is one of the above compositions comprising the excipients added to Form I, and a method comprising the excipients added to Form II.

[0046] 特别优选的实施方式涉及被称为晶型I的虾青素结晶形式，其特征在于至少如下之一 [0046] A particularly preferred embodiment relates to a crystalline form of astaxanthin is known as Form I, wherein at least one of the following

[0047] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :8. 0 + 0. K6. 5±0· 05,6. 3±0· 05,6. 1±0· 05,5. 96±0· 05,5. 58±0· 05,5. 43±0· 05,4. 87±0· 05、4. 32±0· 05,4. 24±0· 05,4. 21±0· 05,4. 07±0· 05,4. 03±0· 05,3. 58±0· 05,3. 50±0· 05， [0047] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:... 8 0 + 0. K6 5 ± 0 · 05,6 3 ± 0 · 05,6. 1 ± 0 · 05,5. 96 ± 0 · 05,5. 58 ± 0 · 05,5. 43 ± 0 · 05,4. 87 ± 0 · 05,4. 32 ± 0 · 05,4. 24 ± 0 · 05,4. 21 ± 0 · 05,4. 07 ± 0 · 05,4. 03 ± 0 · 05,3. 58 ± 0 · 05,3. 50 ± 0 · 05,

[0048] ii)拉曼光谱，其包含在如下位置处的峰：372±2、346±2、333±2、312±2、289±2、234±2、193±2、178±2、133±2、82±201^ ;以及，任选地，至少如下之一 [0048] ii) Raman spectroscopy, which is contained in the peak at the following location: 372 ± 2,346 ± 2,333 ± 2,312 ± 2,289 ± 2,234 ± 2,193 ± 2,178 ± 2, 133 ± 2,82 ± 201 ^; and, optionally, at least one of the following

[0049] iii)显示在212_222°C处发生相转变的DSC扫描；和 [0049] iii) DSC scan showing a phase transition occurs at 212_222 ° C; and

[0050] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为35-45克/升。 [0050] iv) at 20 ° C _25 ° C solubility in dichloromethane distribution of 35-45 g / l.

[0051] 特别优选的实施方式涉及被称为晶型I的虾青素结晶形式，其提供了与图I中给出的X-射线粉末衍射图谱基本上一致的X-射线粉末衍射图。 [0051] A particularly preferred embodiment relates to a crystalline form of astaxanthin crystal Form I is referred to, which is provided in Fig. I given X- ray powder diffraction pattern substantially identical X- ray powder diffraction pattern.

[0052] 特别优选的实施方式涉及被称为晶型I的虾青素结晶形式，其提供了与图2中给出的拉曼光谱基本上一致的拉曼光谱。 [0052] A particularly preferred embodiment relates to a crystalline form of astaxanthin crystal Form I is referred to, which is provided in Figure 2 shows the Raman spectrum of a Raman spectrum substantially uniform.

[0053] 进一步优选的实施方式涉及被称为晶型I的虾青素结晶形式，其特征在于至少如下之一 [0053] A further preferred embodiment relates to a crystalline form of astaxanthin is known as Form I, wherein at least one of the following

[0054] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :8. 0 + 0. K6. 5±0· 05,6. 3±0· 05,6. 1±0· 05,5. 96±0· 05,5. 58±0· 05,5. 43±0· 05,4. 87±0· 05、4. 32±0· 05,4. 24±0· 05,4. 21±0· 05,4. 07±0· 05,4. 03±0· 05,3. 58±0· 05,3. 50±0· 05， [0054] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:... 8 0 + 0. K6 5 ± 0 · 05,6 3 ± 0 · 05,6. 1 ± 0 · 05,5. 96 ± 0 · 05,5. 58 ± 0 · 05,5. 43 ± 0 · 05,4. 87 ± 0 · 05,4. 32 ± 0 · 05,4. 24 ± 0 · 05,4. 21 ± 0 · 05,4. 07 ± 0 · 05,4. 03 ± 0 · 05,3. 58 ± 0 · 05,3. 50 ± 0 · 05,

[0055] ii)拉曼光谱，其包含如下位置的峰：372±2、346±2、333±2、312±2、289±2、 [0055] ii) a Raman spectrum comprising peak following locations: 372 ± 2,346 ± 2,333 ± 2,312 ± 2,289 ± 2,

;以及，任选地，至少如下之一 ; And, optionally, at least one of the following

[0056] iii)显示在212-222°c处发生相转变的DSC扫描；和 [0056] iii) DSC scan showing a phase transition occurs at 212-222 ° c; and

[0057] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为35-45克/升， [0057] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 35-45 g / l,

[0058] 并且包含全-反式-虾青素和至少约13摩尔％的至少一种类胡萝卜素化合物。 [0058] and consists of all - trans - astaxanthin and at least about 13 mole% of at least one carotenoid compounds.

[0059] 进一步优选的实施方式涉及被称为晶型I的虾青素结晶形式，其特征在于至少如下之一 [0059] A further preferred embodiment relates to a crystalline form of astaxanthin is known as Form I, wherein at least one of the following

[0060] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :8. 0 + 0. K6. 5±0· 05,6. 3±0· 05,6. 1±0· 05,5. 96±0· 05,5. 58±0· 05,5. 43±0· 05,4. 87±0· 05、4. 32±0· 05,4. 24±0· 05,4. 21±0· 05,4. 07±0· 05,4. 03±0· 05,3. 58±0· 05,3. 50±0· 05， [0060] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:... 8 0 + 0. K6 5 ± 0 · 05,6 3 ± 0 · 05,6. 1 ± 0 · 05,5. 96 ± 0 · 05,5. 58 ± 0 · 05,5. 43 ± 0 · 05,4. 87 ± 0 · 05,4. 32 ± 0 · 05,4. 24 ± 0 · 05,4. 21 ± 0 · 05,4. 07 ± 0 · 05,4. 03 ± 0 · 05,3. 58 ± 0 · 05,3. 50 ± 0 · 05,

[0061] ii)拉曼光谱，其包含在如下位置处的峰：372±2、346±2、333±2、312±2、289±2、234±2、193±2、178±2、133±2、82±201^ ;以及，任选地，至少如下之一 [0061] ii) Raman spectroscopy, which is contained in the peak at the following location: 372 ± 2,346 ± 2,333 ± 2,312 ± 2,289 ± 2,234 ± 2,193 ± 2,178 ± 2, 133 ± 2,82 ± 201 ^; and, optionally, at least one of the following

[0062] iii)显示在212_222°C处发生相转变的DSC扫描；和 [0062] iii) DSC scan showing a phase transition occurs at 212_222 ° C; and

[0063] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为35-45克/升， [0063] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 35-45 g / l,

[0064] 并且包含全-反式-虾青素和至少约13摩尔％的至少一种类胡萝卜素化合物，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛。 [0064] and consists of all - trans - astaxanthin and at least about 13 mole% of at least one carotenoid compound, a carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin Su, 15-cis - astaxanthin, astaxanthin, semi - astaxanthin and C-25 aldehyde.

[0065] 另一个特别优选的实施方式涉及被称为晶型II的虾青素结晶形式，其特征在于至少如下之一 [0065] Another particularly preferred embodiment relates to a crystalline form of astaxanthin is called Form II, characterized in that at least one of the following

[0066] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :7. 2 + 0. K6. 6±0. 05,6. 5±0· 05,5. 48±0· 05,5. 34±0· 05,5. 27+0. 05,4. 49±0· 05,4. 38±0· 05、4. 12±0· 05,3. 89±0· 05,3. 61±0· 05,3. 56±0· 05,3. 34±0· 05,3. 32±0· 05,3. 22±0· 05，和 [0066] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:.... 7 2 + 0. K6 6 ± 0 05,6 5 ± 0 · 05,5. 48 ± 0 · 05,5. 34 ± 0 · 05,5. 27 + 0. 05,4. 49 ± 0 · 05,4. 38 ± 0 · 05,4. 12 ± 0 · 05,3. 89 ± 0 · 05,3. 61 ± 0 · 05,3. 56 ± 0 · 05,3. 34 ± 0 · 05,3. 32 ± 0 · 05,3. 22 ± 0 · 05, and

[0067] ii)拉曼光谱，其包含在如下位置处的峰：376±2、337±2、314±2、304±2、289±2、206±2、180±2、137±2、107±2、93±201^ ;以及，任选地，至少如下之一 [0067] ii) Raman spectroscopy, which is contained in the peak at the following location: 376 ± 2,337 ± 2,314 ± 2,304 ± 2,289 ± 2,206 ± 2,180 ± 2,137 ± 2, 107 ± 2,93 ± 201 ^; and, optionally, at least one of the following

[0068] iii)显示在225_240°C处发生相转变的DSC扫描；和 [0068] iii) DSC scan showing a phase transition occurs at 225_240 ° C; and

[0069] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为10-30克/升。 [0069] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 10 to 30 g / liter.

[0070] 特别优选的实施方式涉及被称为晶型II的虾青素结晶形式，其提供了与图3中给出的X-射线粉末衍射图谱基本上一致的X-射线粉末衍射图。 [0070] A particularly preferred embodiment relates to a crystalline form of astaxanthin crystal Form II is referred to, which is provided in Figure 3 shows the X- ray powder diffraction pattern substantially identical X- ray powder diffraction pattern.

[0071] 特别优选的实施方式涉及被称为晶型II的虾青素结晶形式，其提供了与图4中给出的拉曼光谱基本上一致的拉曼光谱。 [0071] A particularly preferred embodiment relates to a crystalline form of astaxanthin crystal Form II is referred to, which is provided in Figure 4 shows the Raman spectrum of a Raman spectrum substantially uniform. [0072] 另一个优选的实施方式涉及被称为晶型II的虾青素结晶形式，其特征在于至少如下之一 [0072] Another preferred embodiment relates to a crystalline form of astaxanthin is called Form II, characterized in that at least one of the following

[0073] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :7. 2 + 0. K6. 6±0. 05,6. 5±0· 05,5. 48±0· 05,5. 34±0· 05,5. 27+0. 05,4. 49±0· 05,4. 38±0· 05、4. 12±0· 05,3. 89±0· 05,3. 61±0· 05,3. 56±0· 05,3. 34±0· 05,3. 32±0· 05,3. 22±0· 05，和 [0073] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:.... 7 2 + 0. K6 6 ± 0 05,6 5 ± 0 · 05,5. 48 ± 0 · 05,5. 34 ± 0 · 05,5. 27 + 0. 05,4. 49 ± 0 · 05,4. 38 ± 0 · 05,4. 12 ± 0 · 05,3. 89 ± 0 · 05,3. 61 ± 0 · 05,3. 56 ± 0 · 05,3. 34 ± 0 · 05,3. 32 ± 0 · 05,3. 22 ± 0 · 05, and

[0074] ii)拉曼光谱，其包含在如下位置处的峰：376±2、337±2、314±2、304±2、289±2、206±2、180±2、137±2、107±2、93±201^ ;以及，任选地，至少如下之一 [0074] ii) Raman spectroscopy, which is contained in the peak at the following location: 376 ± 2,337 ± 2,314 ± 2,304 ± 2,289 ± 2,206 ± 2,180 ± 2,137 ± 2, 107 ± 2,93 ± 201 ^; and, optionally, at least one of the following

[0075] iii)显示在225_240°C处发生相转变的DSC扫描；和 [0075] iii) DSC scan showing a phase transition occurs at 225_240 ° C; and

[0076] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为10-30克/升， [0076] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 10 to 30 g / l,

[0077] 并且包含全-反式-虾青素和最多约7摩尔％的至少一种类胡萝卜素化合物。 [0077] and consists of all - trans - astaxanthin and up to about 7 mole% of at least one carotenoid compounds.

[0078] 另一个特别优选的实施方式涉及被称为晶型II的虾青素结晶形式，其特征在于至少如下之一 [0078] Another particularly preferred embodiment relates to a crystalline form of astaxanthin is called Form II, characterized in that at least one of the following

[0079] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :7. 2 + 0. K6. 6±0. 05,6. 5±0· 05,5. 48±0· 05,5. 34±0· 05,5. 27+0. 05,4. 49±0· 05,4. 38±0· 05、4. 12±0· 05,3. 89±0· 05,3. 61±0· 05,3. 56±0· 05,3. 34±0· 05,3. 32±0· 05,3. 22±0· 05，和 [0079] i) X_-ray diffraction pattern, comprising the following lattice plane in meters to 104 ° spacing d:.... 7 2 + 0. K6 6 ± 0 05,6 5 ± 0 · 05,5. 48 ± 0 · 05,5. 34 ± 0 · 05,5. 27 + 0. 05,4. 49 ± 0 · 05,4. 38 ± 0 · 05,4. 12 ± 0 · 05,3. 89 ± 0 · 05,3. 61 ± 0 · 05,3. 56 ± 0 · 05,3. 34 ± 0 · 05,3. 32 ± 0 · 05,3. 22 ± 0 · 05, and

[0080] ii)拉曼光谱，其包含在如下位置处的峰：376±2、337±2、314±2、304±2、289±2、206±2、180±2、137±2、107±2、93±201^ ;以及，任选地，至少如下之一 [0080] ii) Raman spectroscopy, which is contained in the peak at the following location: 376 ± 2,337 ± 2,314 ± 2,304 ± 2,289 ± 2,206 ± 2,180 ± 2,137 ± 2, 107 ± 2,93 ± 201 ^; and, optionally, at least one of the following

[0081] iii)显示在225_240°C处发生相转变的DSC扫描；和 [0081] iii) DSC scan showing a phase transition occurs at 225_240 ° C; and

[0082] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为10-30克/升， [0082] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 10 to 30 g / l,

[0083] 并且包含全-反式-虾青素和最多约7摩尔％的至少一种类胡萝卜素化合物，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛中的至少一种。 [0083] and consists of all - trans - astaxanthin and up to about 7 mole% of at least one carotenoid compound, a carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin Su, 15-cis - astaxanthin, astaxanthin, semi - at least one of astaxanthin and C-25 aldehyde in.

[0084] 另一个特别优选的实施方式涉及被称为晶型II的虾青素结晶形式，其特征在于至少如下之一 [0084] Another particularly preferred embodiment relates to a crystalline form of astaxanthin is called Form II, characterized in that at least one of the following

[0085] i)X_射线衍射图，其包含如下以104°米表示的晶格面间距d :7. 2 + 0. K [0085] i) X_-ray diffraction pattern, comprising the following lattice spacing d to 104 ° in meters:. 7 2 + 0. K

6. 6±0. 05,6. 5±0· 05,5. 48±0· 05,5. 34±0· 05,5. 27+0. 05,4. 49±0· 05,4. 38±0· 05、 6. 6 ± 0. 05,6. 5 ± 0 · 05,5. 48 ± 0 · 05,5. 34 ± 0 · 05,5. 27 + 0. 05,4. 49 ± 0 · 05,4. 38 ± 0 · 05,

4. 12±0· 05,3. 89±0· 05,3. 61±0· 05,3. 56±0· 05,3. 34±0· 05,3. 32±0· 05,3. 22±0· 05，和[0086] ii)拉曼光谱，其包含在如下位置处的峰：376±2、337±2、314±2、304±2、289±2、206±2、180±2、137±2、107±2、93±201^ ;以及，任选地，至少如下之一 4. 12 ± 0 · 05,3. 89 ± 0 · 05,3. 61 ± 0 · 05,3. 56 ± 0 · 05,3. 34 ± 0 · 05,3. 32 ± 0 · 05,3. 22 ± 0 · 05, and [0086] ii) a Raman spectrum comprising peaks at the following location: 376 ± 2,337 ± 2,314 ± 2,304 ± 2,289 ± 2,206 ± 2,180 ± 2,137 ± 2,107 ± 2,93 ± 201 ^; and, optionally, at least one of the following

[0087] iii)显示在225_240°C处发生相转变的DSC扫描；和 [0087] iii) DSC scan showing a phase transition occurs at 225_240 ° C; and

[0088] iv)在20°C _25°C时在二氯甲烷中的溶解度分布为10-30克/升， [0088] iv) at 20 ° C _25 ° C in dichloromethane solubility distribution of 10 to 30 g / l,

[0089] 其中所述虾青素满足表I中所示的如在US-FDA的21 CFR 73. 35中所规定的如下规范： [0089] One such as the following specifications in 21 CFR US-FDA in 73.35 as stipulated in the astaxanthin meet as shown in Table I:

[0090]表 I [0090] Table I

[0091] [0091]

[0092] 进一步的实施方式涉及制备被称为晶型I和晶型II的虾青素结晶形式混合物的方法，所述混合物包含至少5% w/w的晶型I或晶型II，所述方法包含如下步骤： [0092] A further embodiment relates to a method for preparing crystalline form of astaxanthin is called Form I and Form II of the mixture, the mixture comprises at least 5% w / w of Form I or Form II, the the method comprising the steps of:

[0093] i)将包含全-反式-虾青素和约7摩尔％到约17摩尔％至少一种类胡萝卜素化合物的虾青素混合物，在直到所述溶剂沸点的温度下溶解于对虾青素的溶解度为至少I毫克/毫升的溶剂中，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛中的至少一种，并且进一步的步骤选自iia)加入一种反溶剂，iib)通过蒸发，任选地同时通过用反溶剂对溶剂进行交换而除去溶剂，iic)冷却有机溶剂溶液，该有机溶剂溶液任选地具有包含晶型I或II或其混合物的成核剂或晶种，和iii)收集、用反溶剂洗涤并干燥晶体。 [0093] i) will contain the full - trans - astaxanthin and about 7 mole% to about 17 mole% mixture of at least astaxanthin, a carotenoid compounds in the boiling point of the solvent until dissolved astaxanthin The solubility of at least I mg / ml of solvent, the carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin, 15-cis - astaxanthin, astaxanthin, Semi - astaxanthin and C-25 aldehyde in at least one, and further steps selected iia) addition of an anti-solvent, iib) while the anti-solvent by solvent exchange solvent was removed by evaporation, optionally , iic) cooling the organic solvent solution, the organic solvent solution optionally with a Type I or II comprising crystalline nucleating agent or a mixture thereof, or seed, and iii) collecting, antisolvent crystals washed and dried.

[0094] 进一步的实施方式涉及制备被称为晶型I的虾青素结晶形式的方法，其包含如下步骤： [0094] A further embodiment of the preparation of astaxanthin crystal form is called Form I relates to a method comprising the steps of:

[0095] i)将包含全-反式-虾青素和至少约13摩尔％的至少一种类胡萝卜素化合物的虾青素混合物，在直到所述溶剂沸点的温度下溶解于对虾青素的溶解度为至少I毫克/毫升的溶剂中，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛中的至少一种，并且进一步的步骤选自iia)加入一种反溶剂，iib)通过蒸发，任选地同时通过用反溶剂对溶剂进行交换而除去溶剂，iic)冷却有机溶剂溶液，该有机溶剂溶液任选地具有包含晶型I的成核剂或晶种，和iii)收集、用反溶剂洗涤并干燥晶体。 The solubility of astaxanthin and astaxanthin carotenoid mixture of at least one compound of at least about 13 mole percent, in the boiling point of the solvent until dissolved astaxanthin is - [0095] i) will contain the full - trans at least I mg / ml of solvent, the carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin, 15-cis - astaxanthin, astaxanthin, semi - Astaxanthin and C-25 aldehyde in at least one, and further steps selected iia) addition of an anti-solvent, iib) by evaporation, optionally by simultaneous exchange solvent antisolvent to remove the solvent, iic ) cooling the organic solvent solution, the organic solvent solution optionally comprising Form I having a nucleating agent or seed, and iii) collecting, antisolvent crystals washed and dried.

[0096] 进一步的实施方式涉及制备被称为晶型I的虾青素结晶形式的方法，其包含如下步骤： [0096] A further embodiment of the preparation of the crystalline form of astaxanthin is called Form I relates to a method comprising the steps of:

[0097] i)将包含全-反式-虾青素和至少约13摩尔％的至少一种类胡萝卜素化合物的虾青素混合物，在直到所述溶剂沸点的温度下溶解于溶剂中，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛中的至少一种，所述溶剂选自二氯甲烷、三氯乙烷、氯仿、 二甲氧基甲烷、二乙氧基乙烷、二氧杂环戊烷、THF、NMP、N-乙基吡咯烷酮、甲苯、吡啶和二硫化碳，并且进一步的步骤选自iia)加入一种反溶剂，其选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇和水，iib)通过蒸发，任选地同时通过用反溶剂对溶剂进行交换而除去溶剂，iic)冷却有机溶剂溶液，该有机溶剂溶液任选地加入包含晶型I的成核剂或晶种，和iii)收集、用反溶剂洗涤并干燥晶体。 [0097] i) will contain the full - trans - astaxanthin and astaxanthin carotenoid mixture of at least one compound of at least about 13 mole%, and in until the boiling point of the solvent dissolved in a solvent, the carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin, 15-cis - astaxanthin, astaxanthin, semi - astaxanthin and C-25 aldehyde in at least one species, said solvent is selected from dichloromethane, trichloroethane, chloroform, dimethoxymethane, diethoxyethane, dioxolane, THF, NMP, N- ethylpyrrolidone, toluene, pyridine and carbon disulfide and further steps selected iia) addition of an anti-solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and water, iib) by evaporation, optionally At the same time the anti-solvent by solvent exchange to remove the solvent, iic) cooling the organic solvent solution, the organic solvent solution optionally comprising Form I added a nucleating agent or seed, and iii) to collect, and washed with antisolvent dried crystals.

[0098] 进一步的实施方式涉及制备被称为晶型II的虾青素结晶形式的方法，其包含如下步骤： [0098] A further embodiment of the preparation of the crystalline form of astaxanthin crystal form II is referred to relates to a method comprising the steps of:

[0099] i)将包含全-反式-虾青素和基本上最多约7摩尔％的至少一种类胡萝卜素化合物的虾青素混合物，在直到所述溶剂沸点的温度下溶解于对虾青素的溶解度为至少I毫克/毫升的溶剂中，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素，半-虾红素和C-25醛中的至少一种，并且进一步的步骤选自iia)加入一种反溶剂，iib)通过蒸发，任选地同时通过用反溶剂对溶剂进行交换，而除去溶剂，iic)冷却有机溶剂溶液，该有机溶剂溶液任选地加入包含晶型I的成核剂或晶种，和iii)收集、用反溶剂洗涤并干燥晶体。 [0099] i) will contain the full - trans - astaxanthin and astaxanthin mixture is essentially up to about 7 mole percent of at least one carotenoid compounds at temperatures up to the boiling point of the solvent was dissolved in astaxanthin The solubility of at least I mg / ml of solvent, the carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin, 15-cis - astaxanthin, astaxanthin, Semi - astaxanthin and C-25 aldehyde is at least one, and further steps selected iia) addition of an anti-solvent, iib) at the same time by using the anti-solvent by evaporation of the solvent exchange, optionally, be removed solvent, iic) cooling the organic solvent solution, the organic solvent solution optionally comprising Form I added a nucleating agent or seed, and iii) collected, washed and dried crystals antisolvent.

[0100] 进一步的实施方式涉及制备被称为晶型II的虾青素结晶形式的方法，其包含如下步骤： [0100] A further embodiment of the preparation of the crystalline form of astaxanthin crystal form II is referred to relates to a method comprising the steps of:

[0101] i)将包含全-反式-虾青素和基本上最多约7摩尔％的至少一种类胡萝卜素化合物的虾青素溶解于溶剂中，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛中的至少一种，所述溶剂选自二氯甲烷、三氯乙烷、氯仿、二甲氧基甲烷、二乙氧基乙烷、二氧杂环戊烷、THF、NMP, N-乙基吡咯烷酮、甲苯、卩比唳和二硫化碳，并且进一步的步骤选自iia)加入一种反溶剂，iib)通过蒸发,任选地同时通过用反溶剂对溶剂进行交换而除去溶剂，iic)冷却有机溶剂溶液，该有机溶剂溶液任选地加入包含晶型II的成核剂或晶种，和iii)收集、用反溶剂洗涤并干燥晶体。 [0101] i) will contain the full - trans - shrimp astaxanthin and essentially up to about 7 mole percent of at least one carotenoid compounds, astaxanthin is dissolved in a solvent, the carotenoid compound is selected from 9-cis - For astaxanthin, 13-cis-astaxanthin, 15-cis - astaxanthin, astaxanthin, semi - at least one of astaxanthin and C-25 aldehyde, said solvent is selected from dichloro methane, trichloroethane, chloroform, dimethoxymethane, diethoxyethane, dioxolane, THF, NMP, N- ethylpyrrolidone, toluene, and carbon disulfide Jie Li ratio, and further selected in step iia) addition of an anti-solvent, iib) by evaporation, optionally by simultaneous exchange antisolvent and solvent removed solvent, iic) cooling the organic solvent solution, the organic solvent solution optionally containing added polymorph II nucleating agent or seed, and iii) to collect, washed with anti-solvent and dried crystals.

[0102] 进一步的实施方式涉及制备被称为晶型I或晶型I和晶型II混合物的虾青素结晶形式的方法，其包含由如下步骤组成的结晶工序，i)将包含全-反式-虾青素和最多约7摩尔％的至少一种类胡萝卜素化合物的虾青素溶解于溶剂中，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式虾青素、15-顺式-虾青素、虾红素、半-虾红素和C-25醛中的至少一种，所述溶剂选自二氯甲烷、三氯乙烷、氯仿、二甲氧基甲烷、二乙氧基乙烷、二氧杂环戊烷、THF、NMP, N-乙基吡咯烷酮、甲苯、卩比啶和二硫化碳，ii)对所述溶剂进行至少一种选自热、光、氧化剂的处理，并且进一步的步骤选自iiia)加入一种反溶剂，iiib)通过蒸发，任选地同时通过用反溶剂对溶剂进行交换而除去溶剂，iiic)冷却有机溶剂溶液，该有机溶剂溶液中加入或不加入成核剂或晶种，和iv)收集、用反溶剂洗涤并干燥晶体。 [0102] A further embodiment relates to a method for preparing a crystalline form of astaxanthin is known as Form I or Form I and Form II mixture comprising crystallization step consists of the following steps of, i) will contain the whole - trans - For shrimp astaxanthin and up to about 7 mole percent of at least one carotenoid compounds, astaxanthin is dissolved in a solvent, the carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-astaxanthin Su, 15-cis - astaxanthin, astaxanthin, semi - astaxanthin and C-25 aldehyde in at least one of said solvent is selected from methylene chloride, trichloroethane, chloroform, dimethoxyethane methane, diethoxyethane, dioxolane, THF, NMP, N- ethylpyrrolidone, toluene, pyridine and carbon disulfide than Jie, ii) said solvent is at least one selected from heat, light, , oxidizing agent treatment, and further steps selected from iiia) addition of an antisolvent, iiib) while the anti-solvent by solvent exchange to remove the solvent, iiic) by evaporation, optionally cooling the organic solvent solution, the organic solvent solution, with or without added nucleating agent or seed, and iv) the collection, anti-solvent washed and dried crystals.

[0103] 本发明优选的实施方式涉及进一步包含将上述定义的晶型I和II或混合物加工成营养剂型的方法。 [0103] A preferred embodiment of the present invention further relates to a process comprising the Form I and II as defined above or a mixture of nutritional dosage form.

[0104] 另一个实施方式是用于生命科学工业中的给药形式，其包含虾青素、晶型I或II或其混合物。 [0104] Another embodiment is for the life sciences industry in the form of administration, which contains astaxanthin, Form I or II or a mixture thereof.

[0105] 另一个实施方式是用于鱼饲料工业中的给药形式，其包含虾青素、虾青素晶型I或II或其混合物，其中虾青素的含量低于20%重量。 [0105] Another embodiment is used in fish feed industry in the form of administration, which contains astaxanthin, astaxanthin crystal Form I or II or a mixture thereof, wherein the content of astaxanthin is less than 20% by weight.

[0106] 另一个实施方式是用于制备鱼饲料以及用于生命科学工业中的给药形式，其包含虾青素晶型I或II或其混合物的悬浮液。 [0106] Another embodiment for the preparation of fish feed and for the life sciences industry in the form of administration, which contains astaxanthin crystal Form I or II or a mixture of suspension.

[0107] 另一个实施方式是制备用于鱼饲料以及生命科学工业中包含虾青素的给药形式的方法，其中将虾青素晶型I或II或其混合物溶于有机溶剂或油或其混合物中，然后进一步将其加工成所述给药形式。 [0107] Another embodiment is a method for preparing fish feed, and life sciences industries included in the form of administration for astaxanthin, wherein the astaxanthin crystal Form I or II or a mixture thereof in an organic solvent or oil or The mixture was then further processed into the form of administration. [0108] 另一个实施方式是制备用于生命科学工业中包含虾青素的给药形式的方法，其中将虾青素晶型I或II或其混合物溶于有机溶剂或油或其混合物中，然后进一步将其加工成包含亲脂性分散剂的所述给药形式。 [0108] Another embodiment is a method for the preparation of the life sciences industry in the form of administration comprising astaxanthin for, which astaxanthin crystal Form I or II or a mixture thereof in an organic solvent or oil or mixtures thereof, then further processed into a lipophilic dispersant comprising the administration form.

[0109] 另一个实施方式是制备用于生命科学工业中包含虾青素的给药形式的方法，其中将虾青素晶型I或II或其混合物溶于有机溶剂或油或其混合物中，然后进一步将其加工成包含亲水性分散剂的所述给药形式。 [0109] Another embodiment is a method for the preparation of the life sciences industry in the form of administration comprising astaxanthin for, which astaxanthin crystal Form I or II or a mixture thereof in an organic solvent or oil or mixtures thereof, then further processed into a hydrophilic dispersing agent comprising the administration form.

[0110] 另一个实施方式是制备包含虾青素的油性组合物的方法，所述方法包括将晶型I或晶型II或其混合物在100°C到230°C之间的温度下直接溶于食用油和/或鱼油中，从而将其直接引入到鱼饲料粒以及其它应用中。 [0110] Another embodiment is a method for preparing an oily composition comprising astaxanthin, the method comprising the Form I or Form II or a mixture thereof at a temperature of 100 ° C to 230 ° C between the direct dissolution edible oil and / or fish oil, so as to be introduced directly into the fish feed grain and other applications.

[0111] 附图简述： [0111] BRIEF DESCRIPTION:

[0112] 图I表示虾青素晶型I的X-射线衍射图。 [0112] FIG. I represents astaxanthin form I X- ray diffraction pattern.

[0113] 图2表示虾青素晶型I的拉曼光谱。 [0113] Figure 2 shows astaxanthin crystal form I Raman spectroscopy.

[0114] 图3表示虾青素晶型II的X-射线衍射图。 [0114] FIG. 3 shows astaxanthin crystal form II of the X- ray diffraction pattern.

[0115] 图4表示虾青素晶型II的拉曼光谱。 [0115] FIG. 4 shows astaxanthin crystal form II Raman spectroscopy.

[0116] 图5表示包含虾青素晶型I和晶型II混合物的拉曼光谱，以及与其对照的根据虾青素晶型I和晶型II单独光谱计算得出的光谱。 [0116] FIG. 5 shows astaxanthin crystal Form I and Form II alone spectra calculated spectra contain astaxanthin crystal Form I and Form II mixture of Raman spectroscopy, and its control.

[0117] 附图和实施例的详细描述： [0117] the detailed description and examples of:

[0118] 类胡萝卜素是一类由八个类异戊二烯单元组成的烃（胡萝卜素）以及它们的氧化衍生物（叶黄素）。 [0118] Carotenoids are a class of eight isoprenoid units hydrocarbons (carotene) and their oxygenated derivatives (xanthophylls). 类胡萝卜素种类的化合物分为两个主要的组：胡萝卜素和叶黄素。 Carotenoids are divided into two main classes of compounds groups: carotene and lutein. 胡萝卜素是纯的多烯烃，例如β胡萝卜素和番茄红色，而与胡萝卜素相反的是，叶黄素另外还含有官能片段例如羟基、环氧基和氧代基团。 Carotene is pure polyenes, such as β-carotene and tomato red, and carotene contrast, lutein also contains functional fragments such as hydroxyl, epoxy and oxo groups. 叶黄素组的典型代表是斑蝥黄(canthaxanthin)、玉米黄素和奸青素。 Lutein is a typical representative of the group canthaxanthin (canthaxanthin), zeaxanthin and astaxanthin rape.

[0119] 虾青素是3，3'_二羟基-β，β-胡萝卜素-4，4'_ 二酮。 [0119] Astaxanthin is 3,3'_ dihydroxy -β, β- carotene -4,4'_ dione. 合成虾青素的CAS号是7542-45-2并且其是非对映异构体（3S，3'S)、（3R，3'S)和（3R，3'R)1 ： 2 ： I的混合物。 Synthetic astaxanthin CAS number is 7542-45-2 and its non-enantiomer (3S, 3'S) (3R, 3'S) and (3R, 3'R) 1,: 2: I was. 从天然来源分离的虾青素的CAS号是472-61-7。 Isolated from natural sources of astaxanthin CAS number is 472-61-7. 虾青素是一种颜料，其发现在许多甲壳纲(Crustaceae)例如通常的龙奸(Homarus gammarus)中，发现在鲑鱼（Salamo salar)中，发现在火烈鸟的羽毛中（例如，Phoencopterus rubber)。 Astaxanthin is a pigment, which are found in many crustaceans (Crustaceae) such as an ordinary dragon rape (Homarus gammarus) found in salmon (Salamo salar) found in flamingo feathers (for example, Phoencopterus rubber ). 奸青素主要用作各种动物,尤其是鲑鱼、鳟鱼、虾、真鲷、观赏鱼和家禽的饲料成分。 Rape astaxanthin is mainly used for all kinds of animals, especially salmon, trout, shrimp, sea bream, ornamental fish and poultry feed ingredients. 最近，天然虾青素还被用作食品、营养品或化妆品具有抗氧化特性的添加剂。 Recently, natural astaxanthin are also used as food, nutraceutical or cosmetic additives with antioxidant properties. [0120] 奸青素可以通过发酵获得（Biotechnol. Letters 10 (1988)609-614),或者从W0-A89/1997和EP329754中公开的微藻中获得。 [0120] rape astaxanthin can be obtained by fermentation (Biotechnol. Letters 10 (1988) 609-614), or the public from W0-A89 / 1997 and EP329754 obtained in microalgae. W0-A86/6082描述了由天然来源中分离虾青素的方法，其是从甲壳动物的壳中通过萃取而进行的。 W0-A86 / 6082 describes a method for separating from a natural source of astaxanthin, which is from crustacean shells carried out by extraction. US2004253664描述了使用真核微生物进行的类胡萝卜素、叶黄素和脱辅类胡萝卜素的制备。 US2004253664 describes the use of eukaryotic microorganisms carotenoids, lutein and preparation of apo carotenoids. 萃取天然虾青素的替代来源是Aquasta™，其是通过将专有植株的酵母红发夫酵母发酵而制备的产品。 Alternative sources of extraction of natural astaxanthin is Aquasta ™, which is a product by the proprietary yeast plant yeast Phaffia prepared. 获得虾青素的进一步方法是利用化学合成，例如US 5，654，488中所述的。 Further method of obtaining astaxanthin is the use of chemical synthesis, for example, described in US 5,654,488.

[0121] 使用少量（通常约50 μ 1-1000 μ I的奸青素有机溶剂溶液）奸青素结晶形式进行的扫描是在试管或孔板皿（well plate cups)中进行的,通过加入反溶剂或者通过蒸发而使试管/皿中的虾青素结晶，通过测量它们的特征拉曼光谱、X-射线粉末衍射图以及其它物理参数来确定晶体的结构。 [0121] using a small amount (typically about 50 rape astaxanthin organic solvent solution μ 1-1000 μ I) is a crystalline form of astaxanthin scanning rape carried out in a test tube or plate dish (well plate cups) carried out by the addition of anti- a solvent or by evaporation leaving the tube / dish astaxanthin crystals were characterized by measuring their Raman spectroscopy, X- ray powder diffraction pattern and other physical parameters to determine the crystal structure. 使用少量基本上包含多种水平的不同类胡萝卜素化合物的虾青素进行受控制的结晶，出乎意料地产生两种分别形成或者在混合物中一起形成的不同虾青素晶型。 A small amount of astaxanthin containing essentially various levels of different carotenoids compounds were controlled crystallization, unexpectedly produce two separately formed or different astaxanthin crystal form in the mixture formed together. 通过将所测定的拉曼光谱与两种晶型在几个已知重量比的“最佳配比”下的平均单独光谱进行比较，从而确定晶型混合物中单独晶型的含量。 Measured by the Raman spectra and two crystal forms in several known weight ratio of the average individual spectra "optimum ratio" under are compared to determine the crystal mixture in a single crystal of content. 两种单独晶型在混合物中的存在是在“最佳配比”的特征拉曼光谱中反映出来的，其中除了单独晶型I和晶型II的光谱峰以外，没有观察到另外的特征峰。 Two separate crystal forms in the mixture is reflected in the presence of the "best matching" feature out of the Raman spectrum, wherein in addition a separate Form I and Form II of the spectral peaks, no additional characteristic peaks were observed . 考察与工业中使用极性、非极性、质子惰性和质子性溶剂进行的溶剂除去和晶体回收相关的因素，其涉及对虾青素的毒性（例如溶剂残留）、溶解性以及稳定性。 Investigation and industry use of polar and non-polar, aprotic solvent and protic solvent removal and recovery factors associated crystal, which involves the toxicity of astaxanthin (such as residual solvent), the solubility and stability. 它们意外地显示虾青素晶型I或II的形成是独立于所使用的溶剂或结晶方法的，但其实质上取决于类胡萝卜素化合物的存在和浓度。 They unexpectedly showed formation of astaxanthin crystal Form I or II is independent of the use of solvents or crystallization process, but it essentially depends on the presence and concentration of carotenoid compounds. 出乎意料的是，虾青素可以以两种不同的晶型存在并且作为两种晶型的混合物出现，这取决于制备晶体的条件。 Surprisingly, astaxanthin can be in two different crystal forms exist and appear as a mixture of two crystal forms, depending on the conditions for preparing the crystal. 这些内容清楚地表明两种工业应用的晶型以及两种晶型的混合物可以在控制的条件下从虾青素的溶液中制备。 These contents clearly show polymorphs as well as mixtures of two industrial applications of two crystal forms can be prepared from a solution of astaxanthin under controlled conditions.

[0122] 制备用于鱼饲料和营养品应用以及生命科学工业中其它分支的虾青素组合物的已知技术，没有披露制备特定晶型以及特别是两种晶型混合物的可能性，所述特定晶型以及两种晶型混合物明显的特征在于X-射线粉末衍射图和拉曼光谱，以及至少一种其它物理参数例如熔点、在有机溶剂中的溶解度、DSC扫描。 Astaxanthin compositions known techniques [0122] Production of fish feed and nutrition for the application as well as in other branches of the life sciences industry, and did not disclose the possibility of preparation of specific crystal form and, in particular two crystal mixture, said specific crystalline form and a mixture of two distinct polymorphs wherein X- ray powder diffraction pattern and Raman spectroscopy, and at least one other physical parameter such as melting point, solubility in organic solvents, DSC scan. 晶型在有机溶剂和油中具有不同的溶解度，这使得加工和配制虾青素组合物时有了更宽泛的选择。 Polymorphs have different solubility in organic solvents and oils, which makes processing and have a wider choice when astaxanthin compositions may be formulated. 而且，在口服给药之后，晶型可以影响体内的溶解速率并且允许在油性给药媒介中更高的（过饱和的）浓度，这可以提供更高的吸收和生物利用度。 Further, after the oral administration, the crystal form can affect in vivo dissolution rate and allow administration in an oily medium higher (supersaturated) concentration, which can provide a higher absorption and bioavailability.

[0123] 虾青素晶型的X-射线衍射图是使用Bruker D8改进型记录的。 [0123] crystalline form of astaxanthin X- ray diffraction patterns are recorded using a Bruker D8 improved. D值是由在I. 54061(T1CI米波长下的2Θ值计算得到的。Bruker使用软件，EVA10. O版消除了Cu Ka 2福射。拉曼光谱是使用具有1064纳米激光激发波长的Bruker FT-分光计Bruker RFS 100/S记录的。DSC测量是用DSC7型Perkin Elmer差示量热器进行的。 D value is calculated by the 2Θ value I. 54061 (T1CI meter long been under the .Bruker use software, EVA10. O version eliminates Cu Ka 2 blessing shoot Raman spectroscopy is using a 1064 nm laser excitation wavelength of Bruker FT - spectrometer Bruker RFS 100 / .DSC measured S recorded with DSC7 type Perkin Elmer differential calorimeter performed.

[0124] 晶型I具有不规则形状和红色/红褐色外观的晶体惯态，并且相对于晶型II具有更低的熔点，在有机溶剂或油中具有更高的溶解度和溶解速率。 [0124] Polymorph I has an irregular shape and a red / red-brown appearance of the crystal habit, and with respect to Form II has a lower melting point, higher solubility and rate of dissolution in an organic solvent or oil. 晶型I的特征在于其分别在图I和2中给出的X-射线粉末衍射和拉曼光谱。 Form I characterized in that it is given in Figures I and 2 X- ray powder diffraction and Raman spectroscopy. 表2提供了晶型I的特征X-射线粉末衍射。 Table 2 provides a crystalline form I is characterized X- ray powder diffraction. 峰位置通过2-Θ °角和相应的d值给出。 Peak position by 2-Θ ° angle and the corresponding values ​​are given d. 这些位置的标准偏差可以为±5%或更小。 The standard deviation of these positions may be ± 5% or less. 峰强度通过它们的Cps值和相对于最大值的相对强度而给出。 Peak intensity by their Cps value and relative intensity of the maximum value given. 当相对强度< 5%时，该峰被称为“W”，即“非常弱”。 When the relative strength of <5%, the peak is called "W", or "very weak." 相应地5-15%被称为“w” (弱);15-30%被称作“m”（中等)；30-70%为“s”（强）而> 70%被称为“vs” (非常强）。 Accordingly 5-15% is called "w" (weak); 15-30% is called "m" (medium); 30-70% for the "s" (strong) and> 70% is called "vs "(very strong). [0125]表 2 [0125] Table 2

[0127] 表3提供了晶型I的特征拉曼光谱。 [0127] Table 3 provides the characteristics of Form I Raman spectroscopy. 峰位置通过以cm—1表示的波数给出。 Peak position by cm-1 wavenumber represented given. 这些位置的标准偏差可以为±5%或更小。 The standard deviation of these positions may be ± 5% or less. 峰强度通过它们的拉曼强度值以及相对于最大值的相对强度给出。 By their Raman intensity peak intensity value and relative intensity maximum is given. 当相对强度< 5%时，该峰被称为“vw”，即“非常弱”;相应地5-15%被称为 When the relative strength of <5%, the peak is called "vw", or "very weak"; accordingly 5-15% is called

Y (弱);15-30%被称作“m”（中等);30-70%为“s”（强)而> 70%被称为“vs”（非常强）。 Y (weak); 15-30% is referred to as "m" (medium); 30-70% for the "s" (strong) and> 70% is called "vs" (very strong).

[0128]表 3[0129] [0128] Table 3 [0129]

[0130] 晶型I在干燥形式下是稳定的。 [0130] Polymorph I in dry form is stable. 该晶体相对于晶型II可以显示出期望的特性，例如在有机溶剂和油中具有提高的溶解性。 With respect to the crystal Form II can exhibit desired characteristics, e.g., having increased solubility in organic solvents and oils.

[0131] 晶型II具有晶体锋/片样的惯态以及蓝/紫色外观，相对于晶型I具有更高的熔点，在油和有机溶剂中具有更低的溶解度。 [0131] Form II has a crystal front / sheet-like state of inertia and blue / purple exterior, with respect to the crystalline form I has a higher melting point, have a lower solubility in oils and organic solvents. 晶型II的特征在于其分别在图3和4中给出的X-射线粉末衍射和拉曼光谱。 Form II is characterized in that it is given in Figures 3 and 4, X- ray powder diffraction and Raman spectroscopy. 在表4中提供了晶型II的一般X-射线粉末衍射。 It provides general X- ray powder diffraction polymorph II in Table 4 below. 峰位置通过2-θ°角和相应的d值给出。 Peak position by 2-θ ° angle and the corresponding values ​​are given d. 这些位置的标准偏差可以为±5%或更小。 The standard deviation of these positions may be ± 5% or less. 峰强度通过它们的Cps值和相对于最大值的相对强度而给出。 Peak intensity by their Cps value and relative intensity of the maximum value given. 当相对强度< 5%时，该峰被称为“W”，即“非常弱”;相应地5-15%被称为“w”（弱）；15-30%被称作“m”（中等）；30-70%为“s，，（强)而> 70%被称为“vs”（非常强）。 When the relative strength of <5%, the peak is called "W", or "very weak"; accordingly 5-15% is called the "w" (weak); 15-30% is called "m" ( moderate); 30-70% for the "s ,, (strong) and> 70% is called" vs "(very strong).

[0132]表 4 [0132] Table 4

[0135] 在表5中提供了晶型II的一般拉曼光谱。 [0135] provides a general Raman spectra of polymorph II in Table 5. 峰位置通过以cm—1表示的波数给出。 Peak position by cm-1 wavenumber represented given. 这些位置的标准偏差可以为±5%或更小。 The standard deviation of these positions may be ± 5% or less. 峰强度通过它们的拉曼强度值以及相对于最大值的相对强度给出。 By their Raman intensity peak intensity value and relative intensity maximum is given. 当相对强度< 5%时，该峰被称为“vw”，即“非常弱”;相应地5-15%被称为“w”（弱）;15-30%被称作“m”（中等);30-70%为“s”（强)而> 70%被称为“vs”（非常强）。 When the relative strength of <5%, the peak is called "vw", or "very weak"; accordingly 5-15% is called the "w" (weak); 15-30% is called "m" ( Average); 30-70% for the "s" (strong) and> 70% is called "vs" (very strong).

[0136]表 5 [0136] Table 5

[0138] 图5描绘了包含晶型I和晶型II的O. 55 ： O. 45重量比混合物的拉曼光谱。 [0138] Figure 5 depicts O. contains crystalline Form I and Form II of 55: O. 45 weight ratio mixture of Raman spectroscopy.

[0139] 为了制备期望的晶型或两种晶型的混合物，可以将包含至少93%重量的全-反式-虾青素的虾青素溶于适当的溶剂中，并且用作起始原料。 [0139] For the preparation of the desired crystalline form or a mixture of two crystalline form, it can be included at least 93% by weight of the whole - trans - astaxanthin astaxanthin is dissolved in a suitable solvent and used as a starting material . 可以加入适当量的至少一种类胡萝卜素化合物。 It may be added an appropriate amount of at least one carotenoid compound. 可替代地，可以通过控制条件例如温度和溶液的氧化在结晶之前和/或期间现场形成类胡萝卜素化合物。 Alternatively, for example, the oxidation temperature may be in solution prior to crystallization and site / or carotenoid compounds formed during the control condition. 例如，可以在将虾青素溶解在高沸点溶剂期间或之后现场形成类胡萝卜素化合物，所述高沸点溶剂例如是甲苯、食用油和烷醇。 For example, the following compounds carotenoids astaxanthin is dissolved in a high boiling solvent or in the field during the formation of the high-boiling solvent such as toluene, edible oils and alkanols. 可以将包含期望晶型的晶种加入到结晶介质中以加速结晶并且增加期望晶型的产率。 It can include a seed crystal is added to the desired crystallization medium to accelerate and increase the yield of the desired crystalline polymorph.

[0140] 可替代地，期望的晶型或晶型I和晶型II的混合物可以通过控制虾青素生产、萃取或纯化步骤的方法而被制备，其中最终的结晶溶液包含足够量的至少一种类胡萝卜素化合物（复数），其基本上是在形成本说明书所描述的晶型I、晶型II或晶型I和晶型II物理混合物的期望范围内。 [0140] Alternatively, the mixture may be, or the desired polymorph Form I and Form II can be prepared by controlling astaxanthin production, extraction or purification steps of the method are prepared, wherein the final crystallization solution comprises a sufficient amount of at least one carotenoid compound (s), which is essentially formed within a desired range of polymorph I described in this specification, the crystalline polymorph Form II or I and Phase II physical mixture. 晶型I或晶型I和晶型II的混合物还可以在具有高纯度虾青素(即，大于95% )的溶液中制备，然后用例如热和/或光处理该溶液，以形成足够量的类胡萝卜素化合物，从而在最终的结晶之后基本上获得晶型I或晶型I和晶型II的混合物。 Or a mixture of crystalline form I polymorph I and Form II can also be prepared in a solution of high purity astaxanthin (ie, greater than 95%), and then use such as heat and / or light treatment of the solution, to form a sufficient amount carotenoid compounds, so that after the final mixture to obtain a substantially crystalline Form I or crystalline Form I and Form II.

[0141] 应当理解的是，上述结晶方法可以优选在制备晶型I或晶型II之一的合成之后进行。 [0141] It should be understood that the above crystallization method after the synthesis can be preferably Form I or Form II were one. 可替代地，它们也可以在虾青素晶体的纯化或萃取步骤（作为化学合成或从天然产物中分离虾青素化合物的部分）中进行，其中使用至少一个用于制备虾青素晶体的结晶步骤，或者利用溶剂的结晶或重结晶工序。 Alternatively, they may be (as chemical synthesis or part of astaxanthin compounds isolated from natural products) in the purification or extraction steps astaxanthin crystals is carried out, wherein at least one crystalline preparation for astaxanthin crystals step, or by solvent crystallization or recrystallization step.

[0142] 制备虾青素晶型或晶型混合物的起始溶液不需要含有精确量的类胡萝卜素化合物（在所期望的具体晶型范围内），只要在结晶开始时具有足够的浓度，晶型I或II的晶体或其混合物就会随之出现。 [0142] The starting solution for preparing astaxanthin crystal form or crystal mixtures need not contain the exact amount of carotenoid compounds (in particular within the desired range of crystal) with sufficient concentration so long as at the start of crystallization, crystal Type I or II or a mixture thereof will be crystalline appears. 将虾青素溶解在沸腾的溶剂中可以导致作为副产物的类胡萝卜素化合物充分地形成。 The astaxanthin was dissolved in boiling solvent can lead as a byproduct of carotenoid compounds fully formed. 而且通过选择最适当的洗涤溶剂、温度和条件，可以除去未缔合的类胡萝卜素化合物。 And by selecting the most appropriate washing solvent, temperature and conditions, unassociated carotenoid compounds can be removed. 向结晶溶液中加入包含晶型I或晶型II的晶种可以进一步加速期望晶型的形成并且提高产率。 Was added to the crystallization solution contained in the seed crystal Form I or Form II may further accelerate the formation of the desired polymorph and increase the yield.

[0143] 为了制备期望的虾青素晶型I或II或其混合物，可以分别或优选作为混合物加入到全-反式-虾青素中的适当类胡萝卜素化合物是合成的虾青素衍生物例如醚化的或酯化的、氧化或氢化产物、虾青素的顺式异构体。 [0143] In order to prepare the desired astaxanthin crystal Form I or II or a mixture thereof may be added separately or preferably as a mixture to a full - trans - astaxanthin in the carotenoid compounds suitable synthetic astaxanthin derivative for example etherified or esterified, oxidation or hydrogenation product, astaxanthin cis isomer. 该术语包括在虾青素的合成和结晶期间或者在从天然来源萃取虾青素操作期间获得的副产物。 The term includes astaxanthin during synthesis and crystallization or by-products derived from natural sources during the extraction of astaxanthin operation. 类胡萝卜素化合物的形成可以是在次优条件下进行合成的结果，或者可以是在允许将类胡萝卜素化合物浓度控制在期望水平的条件下进行合成、萃取或结晶工序的结果。 The formation of carotenoid compounds can be synthesized the results under suboptimal conditions, or may be allowed to control the concentration of carotenoid compounds were synthesized at the desired level of conditions, extraction or crystallization step results. 优选类胡萝卜素化合物的一种或混合物可以选自9-顺式、13-顺式虾青素以及其它顺式虾青素衍生物（例如15-顺式-虾青素）、虾红素（即β，β-胡萝卜素-3，3'，4，4'_四酮，CAS号为514-76-1)、半-虾红素（3-羟基-β，β-胡萝卜素_3'，4，4' -三酮）和C-25醛（全-反式-3-羟基-4-氧代-12' -脱辅-β-胡萝 One or preferably a mixture of carotenoid compounds can be selected from 9-cis, 13-cis-astaxanthin and other cis-astaxanthin derivative (such as 15- cis - astaxanthin), astaxanthin ( That is β, β- carotene-3,3 ', 4,4'_ -tetrone, CAS No. 514-76-1), semi - astaxanthin (3-hydroxy -β, β- carotene _3' , 4,4 '- trione) and C-25 aldehyde (all - trans-3-hydroxy-4-oxo -12' - apo -β- carrot

卜素-12' -醛，CAS号为72523-68-3)。 BU-12 '- aldehyde, CAS No. 72523-68-3). 它们可以被单独或以任意组合使用。 They can be used alone or in any combination.

[0144] 有几种基于类似原理的结晶方法可以考虑被用来制备晶型I、晶型II或包含晶型I和晶型II的混合物，其是从不同于类胡萝卜素化合物外观和浓度的溶液起始的。 [0144] There are several crystallization methods based on similar principles can be used to consider polymorph I, Form II or a mixture comprising crystalline Form I and Form II was prepared, which is different from the carotenoid compounds from the appearance and concentration initial solution. 本领域技术人员可以确定适当的结晶方法，包括但不限于下述方法。 Those skilled in the art can determine appropriate crystallization method, including but not limited to the following method. 通常，用来制备溶液的适当溶剂是，在结晶开始的温度下溶解至少I毫克/毫升，优选直到10-50毫克/毫升虾青素的溶齐U。 Typically, an appropriate solvent is used to prepare a solution at a temperature of crystallization begins to dissolve at least I mg / ml, preferably up to 10-50 mg / ml homogeneous solution astaxanthin U. 当使用反溶剂时，适当的反溶剂是在结晶的温度下溶解度小于I毫克/毫升的溶剂，并且其与溶解虾青素的溶剂是互溶的。 When using the anti-solvent, anti-solvent is suitable crystallization temperature solubility of less than I mg / mL solvent, and the solvent was dissolved astaxanthin is miscible.

[0145] 在控制的温度条件下由虾青素的非极性质子惰性有机溶液起始，结晶是通过从溶液中除去溶剂，任选地同时用可互溶的极性反溶剂进行交换而引起。 [0145] by a non-polar protic astaxanthin inert organic solution starting crystallization by the solvent is removed from the solution, optionally together with a miscible polar anti-solvent to cause switching at a controlled temperature conditions. 优选的非极性质子惰性溶剂是二氯甲烷。 Preferred non-polar aprotic solvent is methylene chloride. 代替的氯化非极性质子惰性溶剂是例如氯仿、三氯乙烷。 Instead chlorinated apolar aprotic solvents are e.g. chloroform, trichloroethane. 适当的非氯化代替物是二甲氧基甲烷、二乙氧基乙烷和二氧杂环戊烷。 Suitable non-chlorinated substitutes are dimethoxymethane, diethoxyethane and dioxolane. 优选极性反溶剂是甲醇或其它烷醇例如乙醇、正丙醇、异丙醇、正丁醇和叔丁醇。 Preferably a polar anti-solvent is methanol or other alkanols such as ethanol, n-propanol, isopropanol, n-butanol and t-butanol.

[0146] 包含晶型I或晶型II的晶体还可以通过从虾青素极性质子惰性或极性质子性溶剂的虾青素溶液中蒸发除去溶剂而获得。 [0146] crystals contain polymorph I or polymorph II can also be removed by evaporation of the solvent from the solution of astaxanthin astaxanthin polar aprotic or polar protic solvent to obtain. 优选的是对虾青素具有高溶解度以及低沸点的溶齐U。 It is preferred that astaxanthin has a high solubility and low boiling point solvent Qi U. 例如THF和吡啶。 Such as THF and pyridine.

[0147] 引起结晶的另一个方法是冷却非极性质子惰性溶剂的（过)饱和溶液。 [0147] Another method of crystallization caused by cooling of the non-polar aprotic solvent (over) saturated solution. 优选的非极性质子惰性溶剂是二氯甲烷、甲苯或可替代的氯化非极性质子惰性溶剂。 Preferred non-polar aprotic solvents are dichloromethane, toluene or alternative chlorinated apolar aprotic solvent. 对虾青素具有高溶解度的极性溶剂例如四氢呋喃（THF)、Ν-甲基吡咯烷酮（NMP)、Ν-乙基吡咯烷酮（NEP)和吡啶可以被认为是优选的。 Astaxanthin having high solubility polar solvent such as tetrahydrofuran (THF), Ν- methylpyrrolidone (NMP), Ν- ethyl pyrrolidinone (NEP) and pyridine may be considered to be preferred. 期望晶型的结晶速率和产率可以通过向结晶溶液中加入纯晶型的晶种而增加。 Expect crystal crystallization rate and yield can be added to pure crystalline form of the seed crystal to the solution increases.

[0148] 包含晶型I或II的晶体还可以通过加入可互溶的极性反溶剂，将含有期望浓度的全-反式-虾青素和类胡萝卜素化合物在非极性质子惰性、极性质子惰性或极性质子性溶剂中的溶液稀释而获得。 [0148] Crystals comprising Form I or II may also be miscible by the addition of anti-solvent polarity, containing the desired concentration of the whole - in a non-polar aprotic, polar properties of astaxanthin and carotenoid compounds - trans aprotic polar protic solvent or diluent of the solution obtained. 非极性质子惰性溶剂的例子是二氯甲烷、甲苯或代替的氯化溶剂。 Examples of non-polar aprotic solvents are dichloromethane, toluene, or in place of the chlorinated solvents. 反溶剂是像甲醇一样的烷醇。 Anti-solvent like methanol as the alcohol. 适当的极性溶剂的例子是THF、NMP和吡啶。 Examples of suitable polar solvents are THF, NMP and pyridine. 作为反溶剂、可以使用烷醇或者优选地使用水。 As anti solvent, alkanols or preferably water.

[0149] 所产生的晶体通过本领域已知的过滤、自发沉降或离心方法进行收集，任选地用适当的（反）溶剂进行洗涤，优选用冷的烷醇（优选甲醇），并且干燥，优选在真空下。 [0149] The resulting crystals known in the art of filtration, spontaneous sedimentation or centrifugation methods collected, optionally with a suitable (anti) solvent washed, preferably with a cold alkanol (preferably methanol), and dried, preferably under vacuum. 可以对所产生的晶体进行研磨从而获得进一步加工所期望的粒子大小。 Crystals can be produced by grinding to obtain further processing desired particle size.

[0150] 使用上述方法，氯化的溶剂可以用二甲氧基甲烷、二乙氧基乙烷或二氧杂环戊烷代替。 [0150] Using the above method, chlorinated solvents can dimethoxymethane, diethoxyethane or dioxolane instead.

[0151] 随着结晶溶液中类胡萝卜素化合物的浓度从0%增加到最多约7摩尔％并且剩余的类胡萝卜素为全-反式-虾青素时，主要形成晶型II，而另一种晶型I的存在可能低于小于5%的可检测水平。 [0151] As the concentration of the solution in the crystalline carotenoid compound from 0% to up to about 7 mol% and the remaining carotenoids is all-- trans - astaxanthin when forming main polymorph II, whereas the other Form I seed crystals the presence of less than 5% may be lower than the detectable level. 在约7%摩尔类胡萝卜素化合物水平并且剩余的类胡萝卜素为全-反式-虾青素时，在大量晶型II的存在下可能形成微量的晶型I。 In about 7% mole carotenoid levels of the compound and the remaining carotenoids is all-- trans - astaxanthin when, in the presence of a large number of Form II may form a small amount of crystalline form I. 当溶液中类胡萝卜素化合物(复数）的摩尔％从约7摩尔％增加到I 7摩尔％并且总类胡萝卜素的剩余组分为全-反式-虾青素时，获得了包含晶型I和晶型II的混合物，其中晶型I与晶型II的比例随着类胡萝卜素化合物的增加而增加。 When the mole% solution of carotenoid compound (s) is from about 7 mole% to I 7 mole%, and total carotenoids remaining group divided into full - trans - astaxanthin obtained when containing polymorph I and a mixture of crystal form II, the proportion of which polymorph I and polymorph II with increasing carotenoid compounds increases. 在约17摩尔％类胡萝卜素化合物水平并且总类胡萝卜素的剩余组分为全-反式-虾青素时，在大量晶型I的存在下可能形成微量的晶型II。 In about 17 mole% carotenoid levels of the compound and the remaining group total carotenoids into full - trans - astaxanthin when, in the presence of a large number of form I may form a small amount of crystal II. 超过约17摩尔％的类胡萝卜素化合物（复数）并且总类胡萝卜素的剩余组分为全-反式-虾青素时，晶型I占优势并且晶型II的存在可能低于小于5%的可检测水平。 More than about 17 mole% of the carotenoid compound (s) and total carotenoids remaining group divided into full - trans - astaxanthin, there is a polymorph Form II I dominant and may be less than less than 5% detectable levels. 但是，晶型I和/或晶型II形成的程度取决于总的结晶条件。 However, the extent of polymorph I and / or II polymorph formed is dependent on the overall crystallization conditions.

[0152] 根据结晶溶液中类胡萝卜素化合物的水平以及结晶的条件，晶型I和II的混合物可以包含0%到100%的晶型I和100%到0%的晶型II，或者O. 1%到99. 9%的晶型I和99. 9%到O. 1%的晶型II，或者5%到95%的晶型I和95%到5%的晶型II，或者10%到90%的晶型I和90%到10%的晶型II，或者20%到80%的晶型I和80%到20%的晶型II。 [0152] According to the Condition of crystallization solutions carotenoid compounds and crystallization, a mixture of polymorphs I and II can contain from 0% to 100% of the crystalline form I and 100% to 0% of crystal Type II, Type or O. 1% to 99.9% of the crystalline form I and 99.9% to O. 1% of crystal Type II, Type or 5% to 95% of the crystalline form I and 95% to 5% of crystal Type II, Type, or 10% to 90% of the crystalline form I and 90% to 10% of crystal Type II, Type, or 20% to 80% of the crystalline form I and 80% to 20% of the crystalline form II.

[0153] 在优选的实施例中，当类胡萝卜素化合物主要是顺式-虾青素时，可以形成晶型I的晶体，其包含至少约17摩尔％的顺式虾青素（优选地，9-顺式或13-顺式或其混合物）。 [0153] In a preferred embodiment, when the carotenoid compounds are mainly cis - astaxanthin, the Form I crystals can be formed, comprising at least about 17 mole% of cis-astaxanthin (preferably, 9-cis or 13-cis or mixtures thereof). 因此，可能制备包含直到接近100%虾青素的虾青素晶型I，其具有在有机溶剂和油中有益的溶解性特征和较低的熔点。 Therefore, the preparation may contain up to nearly 100% of astaxanthin astaxanthin crystal Form I, which have beneficial in an organic solvent and oil solubility characteristics and low melting point.

[0154] 起始溶液中类胡萝卜素化合物的含量可以高于或低于所产生的晶体，这取决于所使用的结晶程序。 Carotenoid compounds contained in the solution of [0154] may be higher or lower than the initial crystals produced, depending on the crystal used by the program. 当使用升高的温度时，溶液中类胡萝卜素化合物的浓度和晶体将会增加，而晶体的全-反式-虾青素含量会降低。 When using elevated temperature, concentration, and crystal solution carotenoid compounds will increase, and the whole crystal - trans - astaxanthin content will be reduced. 当使用温和的温度条件和/或不同的结晶方法时，类胡萝卜素化合物的水平可以低于晶体。 When using mild conditions of temperature and / or different crystallization method, the level of carotenoid compounds can be less than crystal. 同时，晶体的全-反式-虾青素含量会增加。 At the same time, all crystals - trans - astaxanthin content increases. 而且，制备期望虾青素晶型的最后阶段所使用的洗涤步骤可以从虾青素晶体中除去未缔合的类胡萝卜素化合物。 Moreover, the final stage of preparing the desired wash step astaxanthin crystal forms can be used to remove the non-associated carotenoid compounds from astaxanthin crystal.

[0155] 从包含全-反式-虾青素和超过约17摩尔％类胡萝卜素化合物（复数）的溶液中制备的晶型I，可以包含全-反式-虾青素以及优选至少约13摩尔％的至少一种类胡萝卜素化合物，所述类胡萝卜素化合物选自顺式-虾青素、半-虾红素、虾红素或C-25醛。 [0155] from the group consisting wholly - trans - astaxanthin and more than about 17 mole% carotenoid compounds (plural) was prepared in crystal form I, can contain full - trans - astaxanthin and preferably at least about 13 mol% of at least one carotenoid compound, the compound is selected from cis carotenoid - astaxanthin, semi - astaxanthin, astaxanthin or C-25 aldehyde. 更优选的是9-顺式或13-顺式-虾青素或者15-顺式-虾青素中的一种或其混合物。 More preferably, the 9-cis or 13-cis - astaxanthin or 15- cis - astaxanthin in or a mixture thereof. 当全部晶体都是晶型I并且虾青素包含全-反式-虾青素和仅有的9-顺式或13-顺式-虾青素时，根据水产养殖中采用的纯度定义（这里参考Determination ofstabilized astaxanthinin premixes and fish feeds-version I. I, RocheVitamins Ltd, J. Schierle, N. Faccin,V. Riegert),奸青素可能被认为是100%纯的。 When all crystals are polymorph I and astaxanthin contains a fully - trans - astaxanthin and only 9-cis or 13-cis - astaxanthin when, according to the purity of the definition of aquaculture employed (here Reference Determination ofstabilized astaxanthinin premixes and fish feeds-version I. I, RocheVitamins Ltd, J. Schierle, N. Faccin, V. Riegert), rape astaxanthin may be assumed to be 100% pure.

[0156] 从包含全-反式-虾青素和0%到最大约7摩尔％类胡萝卜素化合物浓度的溶液中制备的晶型II，包含全-反式-虾青素以及小于约7摩尔％的至少一种优选类胡萝卜素化合物，所述类胡萝卜素化合物选自9-顺式-虾青素、13-顺式-虾青素、15-顺式-虾青素、半-虾红素、虾红素或C-25醛。 [0156] from the group consisting wholly - trans - astaxanthin was prepared and 0% to a maximum of about 7 mole% carotenoid compound concentration in the crystal Type II, Type consists of all - trans - astaxanthin and less than about 7 mole preferably at least one carotenoid compounds% of the carotenoid compound is selected from 9-cis - astaxanthin, 13-cis-- astaxanthin, 15-cis - astaxanthin, half - red shrimp Su, astaxanthin or C-25 aldehyde. 更优选的是9-顺式或13-顺式-虾青素中的一种或其混合物。 More preferably, the 9-cis or 13-cis - astaxanthin in or a mixture thereof. 本发明覆盖了符合US-FDA数据库21CFR 73. 35中所描述要求的虾青素，其包含不超过4%的“除虾青素以外的总类胡萝卜素”，并且是晶型II形式的。 The present invention covers compliance with astaxanthin US-FDA 21CFR 73. 35 database as described in claim, which contains no more than 4% of the "other than astaxanthin total carotenoids" and is polymorph Form II. 为了消除疑虑，“除虾 For the avoidance of doubt, "In addition to shrimp

青素以外的总类胡萝卜素”在本发明中被定义为“类胡萝卜素化合物”。优选是符合FDA要求的虾青素，其中“除虾青素以外的总类胡萝卜素”由选自顺式-虾青素、虾红素、半-虾红素和C-25醛中至少一种的类胡萝卜素化合物组成。更优选的是符合FDA要求的虾青素，其中所述“除虾青素以外的总类胡萝卜素”由选自9-顺式-虾青素、13-顺式-虾青素和15-顺式-虾青素的类胡萝卜素化合物组成。 Total carotenoids other than astaxanthin "is defined as in the present invention, the" carotenoid compounds. "Preferably it is in line with FDA requirements astaxanthin, which" in addition to astaxanthin total carotenoids "selected from cis composed of astaxanthin and C-25 aldehyde at least one carotenoid compounds more preferred it is FDA compliant astaxanthin, wherein said "In addition astaxanthin - type - astaxanthin, astaxanthin, half. total carotenoids other than prime "selected from 9-cis - astaxanthin, 13-cis-- astaxanthin and 15-cis - carotene astaxanthin compound classes.

[0157] 晶型可以包含以少量的允许量存在的其它化合物例如溶剂残余物、重金属和降解产物。 [0157] crystalline form may contain small amounts of other compounds in order to allow the amount of such as solvent residues, heavy metals and degradation products.

[0158] 晶型I、晶型II以及两种晶型的混合物适合于被掺入到适于对有机体给药的固体、半固体制剂中。 [0158] polymorph I, polymorph II as well as mixtures of two crystalline forms adapted to be incorporated into a suitable organism administered solid, semi-solid formulation. 固体形式的例子是片剂、颗粒、丸剂、胶囊、粉末等。 Examples of solid forms are tablets, granules, pills, capsules, powders and the like. 半固体形式的例子是乳油、膏剂、凝胶、悬浮液和洗液。 Examples of semi-solid forms are creams, ointments, gels, suspensions and lotions. 它们特别地包括晶型I或晶型II或晶型I和晶型II混合物在油性媒介中的颗粒微粉悬浮液。 In particular, they include polymorph I or polymorph II or polymorph I and Phase II mixture of particles in oily media powder suspension. 优选地，晶体的平均大小在1-5μπι之间的范围内。 Preferably, the average crystal size in the range between 1-5μπι.

[0159] 使用晶型I可以制备的优选给药形式是包含虾青素的油分散组合物，其制备方法被描述在W003/102116中。 Preferred form of administration [0159] The polymorph I can be prepared in oil dispersion composition comprising astaxanthin and its preparation are described in W003 / 102116 in. 由这里所描述的X-射线和拉曼光谱确定的晶型I或晶型II或其混合物，还可以用于制备包含虾青素的水分散组合物，其描述于US2，861，89UUS5, 364，563和US6, 296，877 中。 X- ray and Raman spectra were determined as described herein polymorph I or polymorph II, or mixtures thereof, may also be used in water dispersible compositions comprising astaxanthin, which is described in US2,861,89UUS5, 364 563 and US6, 296,877 in.

[0160] 制备包含虾青素的固体组合物和制剂的通常方法是，在适当赋形剂的存在下将晶型I、晶型II或其混合物溶于有机、水溶性或水不溶性溶剂或其混合物中，接着通过W003/102116中描述的在水中稀释或蒸发工艺将溶剂除去。 [0160] The method of preparation is usually solid compositions and preparations containing astaxanthin, in the presence of a suitable vehicle will polymorph I, Form II or a mixture thereof dissolved in an organic, water-soluble or water-insoluble solvent or mixture, followed by dilution in water or evaporation process W003 / 102116 describes the solvent was removed. 晶型I或II可以这样直接使用，以及通过施加能量而溶于虾青素的油性溶液中。 Form I or II can be used directly, and by the application of energy and soluble oily astaxanthin solution.

[0161] 用于制备溶液以及用于将虾青素晶型I或II或其混合物加工成干燥的虾青素组合物的溶剂，可以是水溶性或水不溶性的。 [0161] for the preparation of solutions and for astaxanthin crystal form I or II, or a solvent mixture into dry astaxanthin composition may be water-soluble or water-insoluble. 水溶性和不溶性溶剂的例子包括上述用来结晶晶型的溶剂的例子。 Water soluble and insoluble solvents include the above-mentioned solvents for crystalline polymorph example. 通过施加热/压力，在结晶期间在常压和环境温度下使用的反溶剂可以被用作虾青素的溶剂（例如异丙醇/水）。 By applying heat / pressure, an anti-solvent during crystallization at atmospheric pressure and ambient temperatures it may be used as a solvent for astaxanthin (e.g., isopropanol / water).

[0162] 赋形剂的优选例子是分散剂、聚合物和合成天然树胶以及纤维素衍生物，其可以是亲水的或者亲脂的。 Preferred examples of [0162] excipients are dispersants, polymers and synthetic natural gums and cellulose derivatives, which may be hydrophilic or lipophilic.

[0163] 固体奸青素组合物包含2. 5重量％到25重量％、优选5重量％到15重量％、更优选7. 5重量％到12. 5重量％之间的总虾青素。 [0163] The solid astaxanthin composition comprises rape 2.5 wt% to 25 wt%, preferably from 5 wt% to 15 wt%, more preferably from 7.5 wt% to 12.5 wt% of total astaxanthin between. 用于组合物中的分散剂的量优选在50重量％到97. 5重量％之间。 Used in the composition in an amount of dispersing agent is preferably 50 wt% to 97.5 wt.% Between. 变化量的赋形剂可以被用作填充剂以组成所要求的重量。 The amount of change can be used as a filler excipient in the composition of the desired weight.

[0164] 适当的亲脂性分散剂是作为亲脂性聚合物被描述于W003/102116中的那些，其适于制备油溶性类胡萝卜素组合物，并且作为亲脂性涂敷材料用作营养品或药物的添加剂以修饰口服固体极性的药物释放。 [0164] Suitable lipophilic dispersing agent is a lipophilic polymer as described in W003 / 102116 those adapted for preparing oil soluble carotenoid compositions and as lipophilic coating material is used as food or pharmaceutical additives to modify the drug release oral solid polarity. 适当的分散剂可以特别地选自乙基纤维素、合成和天然树月旨、松香和树胶。 Suitable dispersing agents may be particularly selected from ethyl cellulose, synthetic and natural tree month purpose, rosin and gum.

[0165] 适当的亲水性分散剂是作为水溶性分散剂被描述于US2861891、US5364563和US6296877中的那些，其中还描述了适于制备水分散类胡萝卜素组合物的方法。 [0165] Suitable hydrophilic dispersants are water-soluble dispersing agent are described in US2861891, US5364563 and US6296877 those, which also describes the preparation of suitable water-dispersible carotenoid composition method. 亲水性分散剂包括但不限于低和高分子量组分的保护性胶体，例如，明胶、鱼胶、淀粉、糊精、植物蛋白、果胶、阿拉伯树胶、酪蛋白、酪蛋白酸酯或这些的混合物，含蛋白的保护性胶体，特别是非胶凝低分子量蛋白质水解物和高分子量胶凝明胶是优选的。 Hydrophilic dispersing agents include, but are not limited to low and high molecular weight component of the protective colloid, such as gelatin, isinglass, starch, dextrin, vegetable proteins, pectin, gum arabic, casein, caseinate or these esters The mixture containing the protein protective colloids, in particular non-gelling protein hydrolyzate and a low molecular weight gelling gelatin of high molecular weight are preferred. 这些以及其它聚（乙烯基醇）、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素、羟丙基纤维素和藻酸盐也被可以使用。 These and other poly (vinyl alcohol), polyvinylpyrrolidone, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and alginates can also be used. 低分子量保护性胶体组分的平均分子量优选为10，000到50，000，特别是15，000到30，000，而高分子量组分具有大于60，000的优选平均分子量。 Low molecular weight protective colloid component is preferably an average molecular weight of 10,000 to 50,000, especially 15,000 to 30,000, and preferably has an average molecular weight component having a molecular weight greater than 60,000. 低分子量的保护性胶体组分的比例为5到95%重量，优选20到80%重量，尤其是30到60%重量。 The proportion of low molecular weight protective colloid component is from 5 to 95% by weight, preferably 20 to 80% by weight, in particular from 30 to 60% by weight. 为了增加最终产物的机械稳定性，便利的方法是将所述胶体与软化剂例如糖或糖醇混合，例如，描述于US 6，296，877中的蔗糖、葡萄糖、乳糖、转化糖、山梨糖醇、甘露糖醇或甘油。 In order to increase the mechanical stability of the final product, e.g., a convenient method is to mix the sugar or sugar alcohol with a colloid softening agent, e.g., described in US 6,296,877 of sucrose, glucose, lactose, invert sugar, sorbitol, alcohol, mannitol or glycerol. 进一步的亲水性分散剂可以选自丽为4000-6000的PEG(聚乙烯基乙二醇）、聚乙烯吡咯烷酮、聚乙烯基醇、交联的聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-聚乙酸乙烯酯共聚物、羟丙基甲基纤维素（HMPC)、羟丙基纤维素（HPC)、羟丙基甲基纤维素邻苯二甲酸酯（HPMCP)、聚丙烯酸酯和聚甲基丙烯酸酯。 Further hydrophilic dispersants may be selected as 4000-6000 Lai PEG (polyethylene glycol group), polyvinylpyrrolidone polyvinyl pyrrolidone, polyvinyl alcohol, cross-linked polyvinyl pyrrolidone - polyvinyl acetate copolymer, hydroxypropylmethylcellulose (HMPC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose phthalate (HPMCP), polyacrylates and polymethacrylates.

[0166] 溶剂或溶剂混合物通过例如喷雾干燥、冷冻干燥、冷冻喷雾干燥、喷雾造粒或超临界流体膨胀除去。 [0166] The solvent or solvent mixture, for example by spray drying, freeze drying, freeze spray drying, spray granulation or supercritical fluid expansion removed.

[0167] 所述晶型适于制备包含如US 6，827，941所述J或H虾青素聚集体的组合物，所述聚集体是通过向过量的水中加入由虾青素晶型I、晶型II或其混合物制备的有机溶剂溶液而沉淀得到的。 [0167] The crystalline form suitable for preparing a composition as described in US 6,827,941 J or H aggregates of astaxanthin, the aggregate by the excess of water is added by the astaxanthin crystal form I , an organic solvent solution of Form II or mixtures of precipitated was prepared.

[0168] 晶型I可以优选地被用于生产根据US 6，093，348的水分散组合物，其中用适当的表面活性剂/水状胶体将类胡萝卜素分散并且在高温和高压下融化从而形成乳化液。 [0168] Form I can preferably be used for the production of an aqueous dispersion according to US 6,093,348 a composition wherein a suitable surfactant / hydrocolloids and dispersing the carotenoid at elevated temperature and pressure in order to melt to form an emulsion.

[0169] 实施例: [0169] Example:

[0170] 以下代表性实施例（1-7)举例说明了制备虾青素晶型I或晶型II或其定义的混合物的方法，其是由不同极性的有机液体溶液起始的，包含已知量的全-反式-虾青素和至少一种指定的类胡萝卜素化合物。 [0170] The following representative examples (1-7) illustrate a method of preparing a mixture of astaxanthin crystal Form I or Form II or defined, which is different from the polarity of the organic liquid solution of the starting, comprising A known amount of whole - trans - astaxanthin and at least one of the specified carotenoid compounds. 实施例（7-9)举例说明了晶型I和/或晶型II或其定义的混合物可以这样被引入给药形式中的方法。 Example (7-9) illustrates the crystal or a mixture of type I and / or II polymorph defined forms of administration may be introduced in this way. 实施例（10-13)举例说明了晶型I或晶型II或其定义的混合物可以被溶于溶剂以制备给药及营养组合物的方法。 Example (10-13) illustrates mixture Form I or Form II or defined may be dissolved in a solvent to prepare a nutritional composition is administered and methods.

[0171] 为了制备期望的晶型,从Sigma (天然奸青素）和Dr. Ehrenstorfer (合成奸青素，分析级）处购买虾青素。 [0171] In order to prepare the desired crystalline form, from Sigma (natural astaxanthin rape) and Dr. Ehrenstorfer (synthetic astaxanthin rape, analytical grade) purchased astaxanthin. 通过HPLC测定化合物的纯度，并且通过X-射线衍射和拉曼光谱表征。 The purity of the compounds characterized by HPLC, and by X- ray diffraction and Raman spectroscopy. 超高纯度的虾青素还可以通过制备HPLC的方式由较低纯度的虾青素获得。 Ultra-pure astaxanthin may also be obtained by preparative HPLC of the lower purity of astaxanthin.

[0172] 实施例I [0172] Example I

[0173] 将40毫克虾青素（97. 2摩尔％的全-反式-虾青素和I. 6摩尔％的9_顺式-虾青素和I. 2摩尔％的13-顺式-虾青素）在30°C下溶于2毫升二氯甲烷（DCM)中，通过在真空下除去溶剂而加工成晶体。 [0173] 40 mg of astaxanthin (97.2 mol% of full - trans - astaxanthin and I. 6 mol% of 9_ cis - astaxanthin and I. 2 mol% of 13-cis - astaxanthin) is dissolved in 2 ml of methylene chloride at 30 ° C under (DCM), and the solvent was removed by in vacuo and processed into crystals. 如图4所示的拉曼光谱显示了晶型II的存在。 Raman spectrum shown in FIG. 4 shows the presence of form II. X-射线衍射图被显示在图3中。 X- ray diffraction diagram is shown in Figure 3. HPLC分析晶体表明99. 2摩尔％的全-反式-虾青素、O. 4摩尔％的9-顺式-虾青素、0.4摩尔％的13-顺式-虾青素，相当于约0.8摩尔％的类胡萝卜素化合物水平。 HPLC analysis showed 99.2 mole% crystal full - trans. - Astaxanthin, O 4 mol% of 9-cis - astaxanthin, 0.4 mol% of 13-cis-- astaxanthin, representing approximately 0.8 mol% of the carotenoid compounds levels.

[0174] 实施例2 [0174] Example 2

[0175] 将20毫克分析级虾青素（97. 2摩尔％的全-反式-虾青素和I. 6摩尔％的9_顺式-虾青素和I. 2摩尔％的13-顺式-虾青素）溶于I毫升吡啶中并在70°C下加热30分钟。 [0175] 20 mg of analytical grade astaxanthin (97.2 mol% of full - trans - astaxanthin and I. 6 mol% of 9_ cis - astaxanthin and I. 2 mol% of 13- cis - astaxanthin) is dissolved in I ml of pyridine and heated at 70 ° C for 30 minutes. 加入8. O毫升冷水之后，用水洗涤所产生的晶体，如在图2中的光谱所示，拉曼光谱显示了晶型I的存在。 8. O ml of cold water after the addition, the resulting crystals were washed with water, as shown in FIG. 2 spectrum, Raman spectrum shows the presence of Form I. X-射线衍射图显示在图I中。 X- ray diffraction pattern shown in Figure I below. HPLC测定证实全-反式-虾青素和顺式-虾青素异构体的总量为100%。 HPLC was confirmed full - trans - astaxanthin and cis - isomers of the total amount of astaxanthin was 100%. 所述虾青素包含78摩尔％的全-反式-虾青素、3摩尔％的9_顺式-虾青素和19摩尔％的13-顺式-虾青素。 The astaxanthin containing 78 mol% of the full - trans - astaxanthin, 3 mol% of 9_ cis - astaxanthin and 19 mole% of 13-cis-- astaxanthin. 类胡萝卜素产物的水平为约22摩尔％。 The level of carotenoids product of about 22 mole%. 类似地，当将吡啶溶液在80°C下加热40分钟时，形成了28摩尔％的13-顺式-虾青素，通过特征X-射线衍射图和拉曼光谱认定所产生的晶体为虾青素晶型I。 Similarly, when the pyridine solution was heated at 80 ° C for 40 minutes, forming a 28 mole% of 13-cis-- astaxanthin, characterized by crystal X- ray diffraction pattern and Raman spectra generated for shrimp identified astaxanthin crystal form I.

[0176] 实施例3 [0176] Example 3

[0177] 将包含97. 2摩尔％的全-反式-虾青素和2. 8摩尔％的顺式-虾青素（进一步包含I. 6摩尔％的9-顺式-虾青素和I. 2摩尔％的13-顺式-虾青素）的20毫克虾青素在室温下溶于I. O毫升吡啶中（溶液I)。 [0177] would contain 97.2 mole% of full - trans - astaxanthin and 2.8 mol% of cis - astaxanthin (further comprising I. 6 mol% of 9-cis - astaxanthin and I. 2 mol% of 13-cis-- I. O ml of pyridine (solution I) astaxanthin) of 20 mg of astaxanthin was dissolved at room temperature. 将实施例2中的20毫克虾青素在室温下溶于I. O毫升吡啶中（溶液2)，所述实施例2中的虾青素包含72摩尔％的全-反式-虾青素和28摩尔％的13-顺式-虾青素。 Example 2 20 mg of shrimp I. O ml of pyridine (solution 2) astaxanthin is dissolved at room temperature, in Example 2 astaxanthin contains 72 mol% of the whole of the implementation - trans - astaxanthin and 28 mole% of 13-cis-- astaxanthin. 将两种溶液以几种比例混合并加入O. 6毫升冷水，通过过滤收集所形成的晶体，用2毫升水洗涤，干燥以后记录拉曼光谱。 The two solutions were mixed in several proportions and O. 6 ml of cold water was added, the crystal formed was collected by filtration, washed with 2 ml of water, after drying recorded Raman spectroscopy. 结果总结在表6中。 The results are summarized in Table 6.

[0178]表 6 [0178] Table 6

[0179] [0179]

[0180] 实施例3清楚地显示，通过使用极性质子性溶剂例如吡啶，晶型I或II或其混合物的形成主要取决于溶液中类胡萝卜素化合物的水平。 [0180] Example 3 clearly shows that by using a polar protic solvent such as pyridine, Form I or II or a mixture thereof is formed mainly depends on the level of carotenoid compounds in solution. 图5描绘了以O. 55 ： O. 45重量比包含晶型I和晶型II混合物的拉曼光谱。 Figure 5 depicts in O. 55: O. 45 weight Raman spectrum comprising Form I and Form II mixture. [0181] 代替地，在加入反溶剂水之前，类胡萝卜素化混合物的浓度可以通过例如加入足够与全-反式-虾青素晶格缔合的已知量的类胡萝卜素化合物而控制，和/或通过加热吡啶溶液从而导致如实施例2中显示的所述类胡萝卜素化合物的形成而现场产生。 [0181] Alternatively, the anti-solvent prior to addition of water, the concentration of carotenoid mixture may be performed by full-such as adding enough - trans - astaxanthin carotenoid compounds associated lattice of a known quantity of controlled, and / or by heating the pyridine solution causing formation as shown in Example 2 of the carotenoid compounds produced and site. 可替代地，期望的晶型或混合物可以通过蒸发溶液、在使用或不使用晶种的情况下冷却晶型I或II的溶液而制备。 Alternatively, the desired crystal form or mixtures may be by evaporating the solution, prepared in the case with or without a seed crystal Form I or II is cooled solution.

[0182] 实施例4 [0182] Example 4

[0183] 将35. 66毫克包含97. 2摩尔％的全-反式-虾青素、I. 6摩尔％的9_顺式-虾青素和I. 2摩尔％的13-顺式-虾青素的虾青素和3. 61毫克包含虾红素的类胡萝卜素化合物溶于24毫升DCM中，通过蒸馏除去DCM，同时用甲醇代替。 [0183] The 35.66 mg containing 97.2 mol% of full - trans - astaxanthin, 6 mol% of cis-9-stage I -. Astaxanthin and I. 2 mol% of 13-cis-- astaxanthin astaxanthin and 3.61 mg of carotenoid compounds containing astaxanthin was dissolved in 24 ml of DCM, DCM is removed by distillation, and replaced with methanol. 收集所产生的晶体并且用冷甲醇洗涤以及真空干燥。 The resulting crystals were collected and washed with cold methanol and dried under vacuum. 拉曼光谱显示存在6 ： 4比例的包含晶型I和晶型II的晶体(将两种晶型的拉曼光谱以几个重量比例进行平均并且与所测量的光谱进行对照）。 Raman spectra showed the presence of 6: 4 ratio comprising crystal Form I and Form II of (the Raman spectra of the two polymorphs in several weight ratios and averaging the measured spectrum with the control). 晶体的HPLC分析显示85. 4% w/w的全-反式-奸青素、O. 4% w/w的9-顺式-奸青素、I. 0%w/w的13-顺式-奸青素、7. 6% w/w的奸红素、I. 9% w/w的半奸红素和3. 6% w/w的C-25醛，相当于类胡萝卜素化合物的水平为约17摩尔％。 HPLC analysis of the crystals show 85. 4% w / w of full - trans - rape astaxanthin, O 4% w / w of 9-cis - rape astaxanthin, I 0% w / w of 13-cis. style. - rape astaxanthin, 7 6% w / w of rape red pigment, I 9% w / w of the half evil red pigment and 3. 6% w / w of the C-25 aldehyde, equivalent carotenoid compounds the level of about 17 mole%.

[0184] 实施例5 [0184] Example 5

[0185] 将40. 3毫克包含80% w/w的全-反式-虾青素、2. 7% w/w的9_顺式-虾青素、2. 7 % w/w的13-顺式-奸青素、O. 8 % w/w的奸红素、5. 5 % w/w的半奸红素和8. 7 % w/w的C-25醛的虾青素溶于24毫升DCM中，并加热至沸腾。 [0185] The 40.3 mg contains 80% w / w of full - trans - astaxanthin, 2 7% w / w of 9_ cis -. Astaxanthin, 2 7% w / w of 13 - cis -. rape astaxanthin, O 8% w / w of the evil red pigment, 5 5% w / w of the semi-evil red pigment and 8. 7% w / w of the C-25 aldehyde astaxanthin solution in 24 ml DCM and heated to boiling. 随着DCM通过蒸馏而被除去，滴加40毫升的MeOH。 As the DCM is removed by distillation, was added dropwise 40 ml of MeOH. 过滤所产生的晶体，然后用0°C的MeOH洗涤并且在室温下真空干燥过夜。 The resulting crystals were filtered, and then washed with MeOH and at 0 ° C with vacuum dried overnight at room temperature. 拉曼光谱显示存在晶形I的晶体。 Raman spectra showed the presence of Form I crystals. 晶体的HPLC分析显示87% w/w的全-反式-虾青素，1.3% w/w的9-顺式-奸青素、I. 5% w/w的13-顺式-奸青素、O. 9% w/w的奸红素、6. 2%w/w的半虾红素和2. 8% w/w的C-25醛，相当于类胡萝卜素化合物的水平为约16摩尔％。 HPLC analysis of the crystals show 87% w / w of full - trans - astaxanthin, 1.3% w / w of 9-cis - rape astaxanthin, I 5% w / w of 13-cis. - Green rape Su, O. 9% w / w of the evil red pigment, 6. 2% w / w of the half astaxanthin and 2. 8% w / w of the C-25 aldehyde, equivalent to the level of carotenoid compound is about 16 mol%.

[0186] 实施例6 [0186] Example 6

[0187] 将196. 7毫克包含80 % w/w的全-反式-虾青素、2. 7 % w/w的9_顺式-虾青素、 [0187] A 196.7 mg containing 80% w / w of full - trans - astaxanthin, 2 7% w / w of 9_ cis -. Astaxanthin,

2. 7 % w/w的13-顺式-奸青素、O. 8 % w/w的奸红素、5. 5 % w/w的半奸红素和8. 7 % w/w的C-25醛的虾青素和203. 3毫克包含97. 2% w/w的全-反式-虾青素、I. 6% w/w的9-顺式-虾青素和1.2% w/w的13-顺式-虾青素的虾青素溶于24毫升DCM中。 2. 7% w / w of 13-cis. - Rape astaxanthin, 8% O w / w of the evil red pigment, 5 5% w / w of the semi-evil red pigment and 8. 7% w / w of C-25 aldehyde astaxanthin and containing 203.3 mg of 97. 2% w / w of full - trans - astaxanthin, I 6% w / w of 9-cis. - astaxanthin and 1.2% w / w of 13-cis-- astaxanthin, astaxanthin is dissolved in 24 ml DCM. 通过蒸馏除去DCM，同时如实施例I中所述用40毫升MeOH代替。 It was removed by distillation DCM, simultaneously as described in Example I replaced by 40 ml MeOH. 拉曼光谱显示存在7 ： 3比例的包含晶型I以及晶型II的晶体。 Raman spectrum shows the presence of 7: 3 ratio comprising Form I and Form II crystals. 晶体的HPLC分析显示91 % w/w的全-反式-虾青素和包含 HPLC analysis of the crystals show 91% w / w of full - trans - astaxanthin and contain

O. 9% w/w的9-顺式-奸青素、O. 5% w/w的13-顺式-奸青素、O. 4% w/w的奸红素、3. 5%w/w的半虾红素和3. 5% w/w的C-25醛的类胡萝卜素化合物，相当于类胡萝卜素化合物的水平为约12摩尔％。 O. 9% w / w of 9-cis - rape astaxanthin, O 5% w / w of 13-cis. - Rape astaxanthin, O 4% w / w of the evil red pigment, 3.5% carotenoid compounds w / w of the half astaxanthin and 3. 5% w / w of the C-25 aldehyde compounds carotenoid levels equivalent to about 12 mole%.

[0188] 实施例7 [0188] Example 7

[0189] 模拟在先的实施例，替换起始溶剂，可以使用如氯仿、三氯乙烷、二甲氧基甲烷、二乙氧基乙烷和二氧杂环戊烷、THF、NMP、NEP和甲苯代替吡啶。 [0189] Simulation of the preceding embodiments, substituted starting solvent, such as chloroform, trichloroethane, dimethoxymethane, diethoxyethane and dioxolane, THF, NMP, NEP instead of pyridine and toluene. 根据包含全_反式-虾青素的结晶溶液（在结晶开始时）中类胡萝卜素化合物的含量，可以从任选地加热的溶液中通过i)蒸发除去溶剂，任选地同时用可互溶的反溶剂代替，ii)向溶液中加入可互溶的反溶剂或者iii)冷却（过饱和）溶液而获得晶型I或晶型II的结晶。 According consists of all _ trans - astaxanthin crystal solution (at the start of crystallization) content of carotenoids compounds can optionally be heated from solution by i) the solvent was evaporated, optionally together with the miscible instead of the anti-solvent, ii) adding to the solution an anti-solvent miscible or iii) cooling (supersaturated) solution to obtain Form I or Form II crystals. 随着结晶溶液中类胡萝卜素化合物的浓度从0%增加到最多约7摩尔％并且总类胡萝卜素剩余组分是全-反式-虾青素时，主要形成晶型II，存在的其它晶型I可能低于小于5%的可检测水平。 As the concentration of the solution in crystalline carotenoid compounds from 0% to up to about 7 mole% and the remaining components of total carotenoids is all-- trans - astaxanthin, the main form crystal Type II, Type other crystal exists Type I may be less than 5% below a detectable level. 在约7摩尔％类胡萝卜素化合物水平并且总类胡萝卜素剩余组分是全-反式-虾青素时，在大量晶型II的存在下可能形成微量的晶型I。 At about 7 mole% carotenoid levels and total carotenoid compounds remaining components of the whole - trans - astaxanthin when, in the presence of a large number of polymorph II may form a small amount of crystalline form I. 当存在的类胡萝卜素化合物（复数）的摩尔％从约7摩尔％增加到约17摩尔％并且总类胡萝卜素的剩余组分为全-反式-虾青素时，获得了包含晶型I和晶型II的混合物，其中晶型I与晶型II的比例增大了。 When the remaining group mole% presence of carotenoid compound (s) is from about 7 to about 17 mole% and the mole% total carotenoids into full - trans - astaxanthin obtained when containing polymorph I and a mixture of Form II, wherein the ratio of crystal form I and form II is increased. 在约17摩尔％类胡萝卜素化合物水平并且总类胡萝卜素的剩余组分为全-反式-虾青素时，在大量晶型I的存在下可能形成微量的晶型II。 In about 17 mole% carotenoid levels of the compound and the remaining group total carotenoids into full - trans - astaxanthin when, in the presence of a large number of form I may form a small amount of crystal II. 超过约17摩尔％的类胡萝卜素化合物（复数）并且总类胡萝卜素的剩余组分为全-反式-虾青素时，晶型I占优势并且晶型II的存在可能低于小于5%的可检测水平。 More than about 17 mole% of the carotenoid compound (s) and total carotenoids remaining group divided into full - trans - astaxanthin, there is a polymorph Form II I dominant and may be less than less than 5% detectable levels. 但是，晶型I和/或晶型II形成的程度取决于总的结晶条件。 However, the extent of polymorph I and / or II polymorph formed is dependent on the overall crystallization conditions. [0190] 实施例8 [0190] Example 8

[0191] 将10克虾青素晶型I或晶型II与90克大豆油混合。 [0191] 10 g of astaxanthin crystal Form I or Form II is mixed with 90 g of soybean oil. 将晶体研磨，所产生的微粉悬浮液适于制备粉末制剂，或者可以使用包含乳化剂的过量油相或水相进行的快速加热程序接着进行冷却而直接溶解在油中。 The crystals are milled, the resulting powder suspension suitable for preparing a powder formulation, or may use an excess oil phase comprising an emulsifier or fast heating program aqueous phase is then cooled directly dissolved in the oil.

[0192] 实施例9 [0192] Example 9

[0193] 将10克虾青素晶型I或晶型II与20克淀粉混合物。 [0193] 10 g of astaxanthin crystal Form I or Form II and 20 g starch mixture. 将粉末进一步加工成适于胶囊填充和压片的可流动颗粒。 It will be further processed into a powder suitable for capsule filling and tabletting flowable particles.

[0194] 实施例10 [0194] Example 10

[0195] 在可加热的接收瓶中，将4克虾青素晶型I或晶型II和I. 54克花生油在30°C下悬浮在28. 8克异丙醇/水（88/12，w/w)的I. 23克乙氧基喹溶液中。 [0195] In a heatable receiving flask, 4 g astaxanthin crystal Form I or Form II and I. 54 grams of peanut oil at 30 ° C under suspended in 28.8 g of isopropanol / water (88/12 , w / w) of I. 23 grams of ethoxypropanol quinoline solution. 在170°C的混合温度下将该悬浮液与58. 7克异丙醇/水（88/12，w/w)混合，停留时间为O. 2秒。 At a mixing temperature of 170 ° C and the suspension was 58.7 g of isopropanol / water (88/12, w / w) mixing, residence time O. 2 seconds. 接着，使所产生的分子性分散的虾青素溶液立即进入进一步的混合室。 Then, the resulting molecular dispersion of astaxanthin solution immediately into the further mixing chamber. 在45°C下向胶体分散形式的沉淀虾青素中加入11. 34克pH调节到9的含水明胶溶液和8. 4克明胶A(lOOBloom，M. ff.=94，000)，所述含水明胶溶液包含4. 2克Gelita Sol P(MW =21，000)和9. 2克蔗糖。 Was added at 45 ° C under the form of a dispersion of colloidal precipitate astaxanthin 11.34 g aqueous gelatin solution was adjusted to pH 9 and 8.4 grams of gelatin A (lOOBloom, M. Ff. = 94,000), the aqueous gelatin solution containing 4.2 g Gelita Sol P (MW = 21,000) and 9.2 g of sucrose.

[0196] 实施例11 [0196] Example 11

[0197] 粉末组合物是通过将I克虾青素晶型I和8克乙基纤维素N4(道氏化学公司)和I克α生育酚溶于90克二氯甲烷（Fluka)中，接着除去溶剂，并使用喷雾造粒制备颗粒而制备的。 [0197] The powder composition is prepared by I g astaxanthin crystal form I and 8 grams of ethyl cellulose N4 (Dow Chemical Company) and I g of α-tocopherol were dissolved in 90 g dichloromethane (Fluka), followed by The solvent was removed, and prepared granules prepared using spray granulation.

[0198] 实施例12 [0198] Example 12

[0199] 粉末组合物是通过将O. 80克虾青素晶型II和8. 4克乙基纤维素Ν4 (道氏化学公司）和O. 80克α生育酚溶于90克二氯甲烷（Fluka)中，接着除去溶剂，并使用喷雾造粒制备颗粒而制备的。 [0199] The powder composition is prepared by O. 80 克 astaxanthin crystal form II and 8.4 g of ethyl cellulose Ν4 (Dow Chemical Company) and O. 80 克 α-tocopherol dissolved in 90 g of methylene chloride (Fluka), followed by removal of the solvent, and spray granulation prepared using the prepared granules.

[0200] 实施例13 [0200] Example 13

[0201] 将620毫克虾青素（晶型II)与200毫升THF在室温下混合并过滤。 [0201] The 620 mg astaxanthin (Form II) and 200 ml THF mixed at room temperature and filtered. 在30分钟内将50毫升该THF溶液滴加到250毫升水中。 Within 30 minutes 50 ml of the THF solution was added dropwise 250 ml of water. 主要形成了虾青素集合的胶体沉淀，其可以通过过滤而收集。 Mainly formed colloidal precipitate astaxanthin set, which can be collected by filtration.