手性分子结晶拆分-晶云药物

1 课程八课程八课程八课程八：：：：手性药物分子的结晶提纯手性药物分子的结晶提纯手性药物分子的结晶提纯手性药物分子的结晶提纯 晶云药物第一届晶型专题技术培训 主讲人主讲人主讲人主讲人：：：：陈敏华博士，首席执行官 Crystal Pharmatech 苏州晶云药物科技有限公司 Email：contact@crystalpharmatech.com 电话：0512-69561921 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 2 提纲 • 手性药物结晶拆分在原料药生产中的重 要性 • 手性药物结晶拆分的原理及工艺研发的 流程和策略：三元相图的应用 • 实例分析: 对于不同种类的对映异构体和 非对映异构体进行手性拆分不同策略的 成功应用 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 3 Enantiomers: stereoisomers which are mirror images of each other (R vs. S) Enantiomeric excess (ee) = (R-S)/(R+S) (0.92 or 92%) Racemate: an equimolar mixture of a pair of enantiomers Diastereomers or diastereoisomers: stereoisomers which are not mirror images of each other (R,S) vs. (R,R) Diastereomeric excess (de) Stereoisomers: mirror image enantiomers, geometric (cis/trans) isomers, and diastereoisomers 手性化合物常用术语 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 4 R-SR-S R-SR-S R-SR-S R R R R R R R R R R R R + S S S S S S S S S S S S R S S R S R R S R S R S Racemate Physical mixture of pure enantiomeric crystals One phase crystalline additional compound Solid solution 对映异构体分类 Conglomerate Racemic Compound PseudoracemateCry sta l Ph arm ate ch Cry sta l Ph arm ate ch 5 •市场上50%的药物是手性分子 • 70%的正在研发的药物是手性分子 •全球销量最好的10个药物中，9个是手性分子 •对于手性药物来说，生产和制备光学纯的对映 异构体非常重要，因为不同的对映异构体可能有 非常不同的生物活性 手性药物的一些事实 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 6 美国药监局对于新的手性药物 开发的指南 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 7 不同对映异构体具有相同活性的 一些手性药物 • Both enantiomers of dobutamine are positive inotropes; • Both ibuprofen enantiomers are anti- inflammatory agents; • Both enantiomers of warfarin and phenprocoumon are anticoagulants; • The enantiomers of bupivicaine both produce local anesthesia; http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 8 • Granulocytopenia is related to the d-isomer of levodopa; vomiting is caused by the d-isomer of levamisole; and myasthenia gravis symptoms were no longer observed when the d-isomer was removed from d,lcarnitine. 不同对映异构体具有不同生物活性 的手性药物 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 9 Hypothetical Interaction between the 2 Enantiomers of A Chiral Drug and Its Binding Site http://www.psychiatrist.com/pcc/pccpdf/v05n02/v05n0202.pdf Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 10 • Although it is now technologically feasible to prepare purified enantiomers, development of racemates may continue to be appropriate. However, currently available information suggests that the following should be considered in product development: – Appropriate manufacturing and control procedures should be used to assure stereoisomeric composition of a product, with respect to identity, strength, quality and purity. Manufacturers should notify compendia of these specifications and tests. – Pharmacokinetic evaluations that do not use a chiral assay will be misleading if the disposition of the enantiomers is different. Therefore, techniques to quantify individual stereoisomers in pharmacokinetic samples should be available early. If the pharmacokinetics of the enantiomers are demonstrated to be the some or to exist as a fixed-ratio in the target population, an achiral assay or an assay that monitors one of the enantiomers may be used, subsequently. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm 美国药监局对于新的手性药物 开发的指南 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 11 Some Examples of Chiral Psychiatric Drugs Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 12 得到纯手性药物的主要途径 + chiral resolving agents Diastereomeric salts Crystallization/ dissolution Salts with desirable ee Pure compound in desirable form Compounds (0% ee) Asymmetric synthesis Enantiomeric mixtures (80-96% ee) Crystallization /dissolution Compounds with desirable ee Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 13 如何进行手性药物结晶提纯工艺的开发？ 现状现状现状现状 • 开发工艺耗时太长，很多随机的实验 • 缺少对手性分子晶型和所属体系的系统了解 • 对手性结晶提纯的工艺的可重复性和可放大性没有把 握，缺少对工艺风险的预测（不知道结晶提纯根据的是 动力学还是热力学原理） 利用三元相图指导结晶工艺开发利用三元相图指导结晶工艺开发利用三元相图指导结晶工艺开发利用三元相图指导结晶工艺开发 • 可以全面理解结晶提纯的原理和过程 • 了解通过结晶工艺提高手性纯度的可能性 • 确定最佳的结晶工艺条件，预测能够提纯到的最高手性 纯度以及对应的产率 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 14 两篇利用三元相图指导手性药物结 晶提纯工艺开发的文献 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 15 S0 10 20 30 40 50 60 70 80 90 100 Solvent 0 10 20 30 40 50 60 70 80 90 100 R 0 10 20 30 40 50 60 70 80 90 100 三元相图的基础知识 • Q represents 50% S, 20% solvent and 30% R. • T represents 80% S, 0% solvent and 20% R. • Any point on the dashed line will represent a system with same ratio of S to R. Q T Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 16S 0 10 20 30 40 50 60 70 80 90 100 Solvent 0 10 20 30 40 50 60 70 80 90 100 R 0 10 20 30 40 50 60 70 80 90 100 A B C solid S solid R S, R, Solvent Add solvent solid S solid R solution Separate the solution and solid phase Q P S T 用三元相图示意手性分子结晶/ 溶解提纯的工艺流程 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 17 D Solvent U A' A S E (a) S DU A' A E (b) r Solvent E' A' A S r A' A A' A Solvent 1 2 3 D (c) U A' A S r A' A A' A Solvent 1 2 3 D (c) U 对映异构体的三元相图 Conglomerate Racemic compound Pseudoracemate Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 18 S Solvent R E Conglomerate系统的三元相图 2var +Π−= Ciance Gibbs Phase Rule: C=3 Fix Pressure 1var +Π−= Ciance Variance in Grey F G 2 1 2 Blue solid line represents the saturated solution curve Region ERS: Both R and S are saturated. Region EFS: R is unsaturated and S is saturated. Region AF’E’EF: Both R and S are unsaturated. A F’ Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 19 S Solvent R R-S E’ Region EDS: Both R-S and S are saturated. Region EFS: R-S completely dissolves in solution and S is saturated. Region E’DE: R-S is saturated and either R or S is unsaturated. Region AF’E’EF: Both R-S and S are unsaturated. F D F’ 2var +Π−= Ciance Gibbs Phase Rule: C=3 Fix Pressure 1var +Π−= Ciance 2 1 1 2 2 Blue solid line represents the saturated solution curve Variance in Grey A E Racemic Compound系统的三元相图 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 20 Develop TPD Conglomerate Racemic compound ee of starting solids > ee of eutectic point ee of eutectic point > minimum ee required for product > ee of starting solids Minimum ee required for product > ee of eutectic point > ee of starting solids (Enriched in solid) (Enriched in solid) (Enriched in supernatant) XRPD, DSC, TG Determine the thermodynamically most stable form of racemate? Determine Type of racemate? Solid Solution Make racemate 1 2 3 6 4 5 7 8 (a) (b) (c) 对映异构体的结晶提纯工艺 开发流程 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 21 Conglomerate System Vmin = )1( ][2 1 0ee U eu − ⋅ D Solvent U A' A S E ( ) ) 1 1 (1 ][ ][][ ][21 0 0 ee ee U DD DV eu pureeu pure + ⋅      −⋅ − +⋅−Yield (at V≥Vmin) = Yield max = 0 0 1 2 ee ee + (1) (2) (3) M 三元相图的深入理解： Conglomerate Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 22 Racemic compound system (when the starting solid has ee higher than that of eutectic) Vmin = )1( ][2 1 0ee U eu − ⋅ )1)(1( )1)(1( 1 0 0 max eu eu eeee eeee Yield −+ +− −= S D Solvent U A' A EE' r p2 Yield (at V≥Vmin) = (4) (5) (6) Vmin represents the volume of solvent (expressed in ml of solvent) to be added to one milligram of solid to reach point M. [D]pure represents the solubility of desired enantiomer in mg of solid per ml of solvent. M ( ) ) 1 1 (1 ][ ][][ ][21 0 0 ee ee U DD DV eu pureeu pure + ⋅      −⋅ − +⋅− Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 23 Racemic compound system (when the starting solid has ee lower than that of eutectic)       − eueu UD ee ][][ 0 Vmax = V D eu ⋅ + 00.5ee0.5 ][Yield(at V≤Vmax) = Yield(at V=Vmax) = )1( )(1ee 0 0 eeee ee eu eu + + (7) (8) (9) Vmax represents the volume of solvent (expressed in ml of solvent) to be added to 1 mg of solid to reach point M. ee0 represents the ee of starting solids whose ee is to be upgraded. eeeu represents the ee of eutectic point. [D]eu and [U]eu represent the concentration of desired enantiomer and undesired enantiomer (mg of solids per ml of solvent) at the eutectic point respectively. V represents the volume of solvent ( in ml) added to one mg of solid. S D Solvent U A' A EE' p 1r MCry sta l Ph arm ate ch Cry sta l Ph arm ate ch 24 案例分析Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 25 Desired enantiomer: (S, S) Undesired enantiomer: (R, R) By asymmetric synthesis, API solids with 92-96% ee can be produced, how to upgrade the ee to above 98%? Compound I 案例分析1: A racemic compound system (with high ee for eutectic point) N H CH 3 O CH 3 CH 3 O N F F F Cl N Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 26 纯对映异构体 vs. 消旋体的物理性质 Different DSC Different XRPD Most likely, the racemate is racemic compound. To be confirmed by solubility ternary phase diagram... Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 27 S/mgR/mg 2:3 IPAC:Heptane (v:v) /0.1 ml 7.2 mg/ml S 7.2 mg/ml R Eutectic point: 98.80% ee 297.6 mg/ml S 1.79 mg/ml R E racemate A ee upgrade of Compound I Form B Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 28 Ternary phase diagram of Form B in 2:3 IPAC:Heptane (v:v) at 25 C 98.80% ee 94% ee P1 P2 98.0% ee Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 29 Based on the above equations, given a starting mixture with ee of 94%, V max is 0.00318 and yield is 97.6% at V=V max . This means by adding 0.00318 ml of 2:3 (v:v) IPAC: Heptane solvent to 1 mg of starting enantiomeric mixture with 94% ee at 25.0 C, at equilibrium, the ee will be upgraded to 98.80% with a yield 97.6%.       − ee UD ee )()( 0 = 0.00338 ee0Vmax = V⋅ + 00.5ee0.5 6.297 Yield V≤Vmax = Optimal process to upgrade ee in 2:3 IPAC:Heptane (v:v) at 25 C Feasibility and strategy: The ee of eutectic point (98.80%) is higher than that of starting solids (~ 94%-96%). Therefore, the ee can be upgraded to a maximum value of 98.80% in the supernatant by dissolution. Determine the optimal solvent/solid ratio and the corresponding yield:Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 30 Chiral amide (penultimate) API 92-96% ee 92-96% ee Dissolution Filter recrystallization API > 98% ee Reaction crystallization Reaction crystallization (ee upgrade by dissolution of API) Chiral amide (penultimate) API >99% ee >99% ee Reaction crystallization Reaction crystallization (ee upgrade by crystallization of penultimate) ee upgrade in chiral amide crystallization step was achieved when a new anhydrous crystalline form of chiral amide enantiomer was discovered. Prior to the discovery of the anhydrous crystalline form, chiral amide crystallized as a mixture of MTBE solvate and amorphous, with no ee upgrade. New ee upgrade process was implemented in the manufacturing process. 中间体新晶型的发现改变了 手性分子的结晶提纯工艺 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 31 D (mg)0 10 20 30 40 50 60 70 80 90100 Ethanol (0.1 ml) 0 10 20 30 40 50 60 70 80 90 100 U (mg) 0 10 20 30 40 50 60 70 80 90 100 Composition of total system Composition of Supernatant E D (mg)0 10 20 30 40 50 60 70 80 90100 Ethanol (0.1 ml) 0 10 20 30 40 50 60 70 80 90 100 U (mg) 0 10 20 30 40 50 60 70 80 90 100 Composition of total system Composition of Supernatant E ee upgrade of Compound II DIPA Salt 案例分析2：A racemic compound system (with low ee for eutectic point) Eutectic point: ee: 30.3% C(R): 5.36 mg/ml R C(S): 2.87 mg/ml S C(R ):4.76 mg/ml Temp: 25 C N SO O OF Cl CH3 O- Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 32 )1( ][2 1 0ee U eu − ⋅ Feasibility and strategy: ee of eutectic point is 30.3%, lower than that of starting solids (92% to 96% ee). Therefore, ee can be upgraded to 100% in the solid phase by adding Vmin or more amount of solvents to the solids. = 0.174 (1-ee0) Based on above, given a starting enantiomeric mixture with 94% ee, V min can be determined to be 0.010 and the yield is 94.4 % at V=V min . This means that by adding 0.010 ml of EtOH to 1 mg of starting enantiomeric mixture with 94% ee at 25.0 C, at equilibrium, the ee of D will be upgraded to 100% in the solid phase with a yield of 94.4 %. Vmin = Optimal process to upgrade ee of DIPA Salt in ethanol at 25 C )1)(1( )1)(1( 1 0 0 max eu eu eeee eeee Yield −+ +− −= Determine the optimal solvent/solid ratio and the corresponding yield:Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 33 案例分析三: A conglomerate System ee upgrade of compound III freebase D (mg)0 10 20 30 40 50 60 70 80 90 100 1:3 (v:v) IPA:Heptane (0.1 ml) 0 10 20 30 40 50 60 70 80 90 100 U (mg) 0 10 20 30 40 50 60 70 80 90 100 Composition of supernatant D (mg)0 10 20 30 40 50 60 70 80 90 100 1:3 (v:v) IPA:Heptane (0.1 ml) 0 10 20 30 40 50 60 70 80 90 100 U (mg) 0 10 20 30 40 50 60 70 80 90 100 Composition of supernatant 25.0 C 45.0 C C(R) =5.6 mg at 25 C Eutectic point: C(S) =6.0 mg/ml C(R) = 6.0 mg/ml C(R) =14.0 mg Eutectic point: C(S) =19.1 mg/ml C(R) =19.1mg/ml NH 2 N O N N N F F F F F F Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 34 ee can be upgraded to 100% in the solid phase by adding Vmin or more solvents to the starting solid. Based on the TPD at 45 C, the solubility of pure conglomerate is 14.0 mg of R and 14.0 mg of S per ml of solvent and that of pure enantiomer R is 10.4 mg per ml of solvent. Therefore, similar Vmin and yield at V≥Vmin can be calculated based on equations (7) and (8). )1( ][2 1 0ee U eu − ⋅ Vmin = = 0.113 (1-ee0) Yield max = 0 0 1 2 ee ee + Optimal process to upgrade ee of Compound III freebase in 1:3 (v:v) IPA:Heptane at 25 C or 45 C Feasibility and strategy: Determine the optimal solvent/solid ratio and the corresponding yield: Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 35 D Solvent U E2 1 2 非对映异构体的三元相图 2var +Π−= Ciance Gibbs Phase Rule: C=3 Fix Pressure 1var +Π−= Ciance Variance in Bold The ternary phase diagram is not symmetric due to different solubility of two diastereomers. Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 36 Vmin = )1( ][2 1 0de U eu − ⋅ ( ) ) 1 1 (1 ][ ][][ ][21 0 0 de de U DD DV eu pureeu pure + ⋅      −⋅ − +⋅−Yield (at V≥Vmin)= )1)(1( )1)(1( 1 0 0 eu eu dede dede −+ +− −Yield (at V=Vmin)= Yield is defined as the ratio of desired diastereomer in the solid phase to the desired diastereomer in the total system. de represents the diastereomeric excess. Define the optimal ratio and predict the yield based on the ternary phase diagram Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 37 OH NH 2 OH NH 2 (1R,2S)-(+)-cis- (1S,2R)-(-)-cis- MW=149.19 Compound IV API CAI Four possible isomers of compound IV CAI salt API(R,R,R)-CAI(R,S): D-d API(S,S,S)-CAI(R,S): U-d API(R,R,R)-CAI(S,R): D-u API(S,S,S)-CAI(S,R): U-u Assuming the crude free acid has ee ~ 92% and CAI salt has ee ~ 99%, then upon salt formation, there will be: D-d: 95.52% U-d: 3.98% D-u: 0.48% U-u: 0.02% API has three chiral centers. 案例分析四: 非对映异构体的手性提纯 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 38 Ternary Plot D-d /mg0 10 20 30 40 50 60 70 80 90 100 Solvent (12.6:87.4 (v:v) toluene:heptane plus various impurities) /ml 0 10 20 30 40 50 60 70 80 90 100 U-d /mg 0 10 20 30 40 50 60 70 80 90 100 Total composition Supernatant Mother liquor from process Eutectic C(D-d): 1.0 mg/ml C(U-d): 2.07 mg/ml de: -34.9% Pure D-d: C(D-d) ~ 0.92 mg/ml Temperature: 23.0 C Starting Solvent: Washed mother liquor (22.8% de, 2.02 g/l) Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 39 Ternary Plot D-d (mg) 0 10 20 30 40 50 60 70 80 90 100 Solvent from ML (237573-251) (0.1 ml) 0 10 20 30 40 50 60 70 80 90 100 U-d (mg) 0 10 20 30 40 50 60 70 80 90 100 Supernatant composition Total system Eutectic: D-d: 19.0 mg/ml U-d: 37.7 mg/ml de: -33.04% Starting solvent: Mother liquor (61.5% de, 17.7 g/l) Temperature: 23.0 C Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 40 • Eutectic de of the diastereomeric system is relatively independent of the solvent composition/impurity concentration and it is very low ~ -34%. • Low eutectic de suggests thermodynamically the undesired diastereomer can be rejected in the supernatant and pure desired diastereomer can be obtained in the solids upon crystallization. • The optimal solvent/solid ratio and the yield can be pre-defined and calculated. 通过结晶提纯的可行性和策略 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 41 总结 初级经济法重点总结下载党员个人总结TXt高中句型全总结.doc高中句型全总结.doc理论力学知识点总结pdf •三元相图是理解手性药物结晶提纯工艺的强有力的工具。 •根据对映异构体或者非对映异构体系统的三元相图，一个 手性药物分子通过结晶或者溶解的方法得到提纯的可行性 可以立刻确定，同时三元相图可以协助我们找到最优化的 结晶工艺条件。 •手性药物的手性提纯可以在原料药最后一步的结晶工艺中 实现，也可以通过中间体的结晶工艺实现。有时通过对手 性药物中间体的结晶，可能可以将一个很难提纯的手性药 物通过很简单的方法得以提纯。 •手性药物的结晶提纯有时会受到结晶动力学的很大影响， 不要忽略。 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 42 晶云药物晶云药物晶云药物晶云药物可以帮助您开发出手性药物结晶提纯手性药物结晶提纯手性药物结晶提纯手性药物结晶提纯的工艺，如 果您有这方面的任何问题，请随时和我们联系咨询！ 苏州晶云药物科技有限公司 Email：contact@crystalpharmatech.com 电话：0512-69561921 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 43 药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息药物晶型研究和药物固态信息 研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业研发领域专业CROCROCROCROCROCROCROCRO 晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司晶云药物科技有限公司 Crystal Pharmatech IncCrystal Pharmatech Inc Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 44 公司使命公司使命公司使命公司使命公司使命公司使命公司使命公司使命 �为全球各制药公司提供药物晶型研药物晶型研药物晶型研药物晶型研 究究究究和药物固态研发药物固态研发药物固态研发药物固态研发领域的最佳技术 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 ，并成为该领域的领导者。Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 45 公司简介公司简介公司简介公司简介公司简介公司简介公司简介公司简介 � 国内第一家专注于药物晶型研究的公司国内第一家专注于药物晶型研究的公司国内第一家专注于药物晶型研究的公司国内第一家专注于药物晶型研究的公司，，，，为全球制药公为全球制药公为全球制药公为全球制药公 司提供药物晶型筛选和研究领域的专业技术服务司提供药物晶型筛选和研究领域的专业技术服务司提供药物晶型筛选和研究领域的专业技术服务司提供药物晶型筛选和研究领域的专业技术服务 � 研发团队晶型研究经验丰富研发团队晶型研究经验丰富研发团队晶型研究经验丰富研发团队晶型研究经验丰富，，，，技术力量雄厚技术力量雄厚技术力量雄厚技术力量雄厚，，，，博士博士博士博士40%40%40%40%，，，， 硕士硕士硕士硕士40%40%40%40%，，，，本科本科本科本科20%20%20%20% � 核心团队成员过去在美国默克核心团队成员过去在美国默克核心团队成员过去在美国默克核心团队成员过去在美国默克，，，，罗氏等全球领先的制药罗氏等全球领先的制药罗氏等全球领先的制药罗氏等全球领先的制药 公司直接负责和从事药物晶型研究和药物固态研发公司直接负责和从事药物晶型研究和药物固态研发公司直接负责和从事药物晶型研究和药物固态研发公司直接负责和从事药物晶型研究和药物固态研发，，，，拥拥拥拥 有在该领域有在该领域有在该领域有在该领域40404040多年的丰富实战经验多年的丰富实战经验多年的丰富实战经验多年的丰富实战经验，，，，曾共同负责和管理曾共同负责和管理曾共同负责和管理曾共同负责和管理 过超过过超过过超过过超过200200200200个药物分子的晶型研究个药物分子的晶型研究个药物分子的晶型研究个药物分子的晶型研究，，，，拥有拥有拥有拥有40404040多项药物晶型多项药物晶型多项药物晶型多项药物晶型 专利专利专利专利，，，，在各类国际学术期刊发 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf 过在各类国际学术期刊发表过在各类国际学术期刊发表过在各类国际学术期刊发表过80808080多篇文章多篇文章多篇文章多篇文章 � 配备了全球领先的晶型筛选和研究的各种固态分析仪器配备了全球领先的晶型筛选和研究的各种固态分析仪器配备了全球领先的晶型筛选和研究的各种固态分析仪器配备了全球领先的晶型筛选和研究的各种固态分析仪器 � 致力于提供研发方案致力于提供研发方案致力于提供研发方案致力于提供研发方案，，，，而不是仅仅提供实验数据而不是仅仅提供实验数据而不是仅仅提供实验数据而不是仅仅提供实验数据 Cry sta l Ph arm ate ch Cry sta l Ph arm ate ch 46 晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器晶云的药物固态表征仪器 固态核磁共振固态核磁共振固态核磁共振固态核磁共振(ssNMR)(ssNMR)(ssNMR)(ssNMR)XXXX----射线粉末衍射仪射线粉末衍射仪射线粉末衍射仪射线粉末衍射仪 (XRPD)(XRPD)(XRPD)(XRPD) 热重分析仪热重分析仪热重分析仪热重分析仪(TGA)(TGA)(TGA)(TGA) 差示扫描量热仪差示扫描量热仪差示扫描量热仪差示扫描量热仪(DSC)(DSC)(DSC)(DSC) Cry