Development and prospects of predicting drug polymorphs technology / 药学学报

Most chemical medicines have polymorphs. The difference of medicine polymorphs in physicochemical properties directly affects the stability, efficacy, and safety of solid medicine products. Polymorphs is incomparably important to pharmaceutical chemistry, manufacturing, and control. Meantime polymorphs is a key factor for the quality of high-end drug and formulations. Polymorph prediction technology can effectively guide screening of trial experiments, and reduce the risk of missing stable crystal form in the traditional experiment. Polymorph prediction technology was firstly based on theoretical calculations such as quantum mechanics and computational chemistry, and then was developed by the key technology of machine learning using the artificial intelligence. Nowadays, the popular trend is to combine the advantages of theoretical calculation and machine learning to jointly predict crystal structure. Recently, predicting medicine polymorphs has still been a challenging problem. It is expected to learn from and integrate existing technologies to predict medicine polymorphs more accurately and efficiently.

Pharmacokinetics of Three Kinds of Mangiferin Polymorphs in Rats / 医药导报

Objective To study the mangiferin absorption process of mangiferin polymorphs in SD rats thus to find out the optimal crystal form and explore the factors that may affect the clinical effects of mangiferin. Methods Each rat was given one of three crystal forms of mangiferin. Plasma concentration of mangiferin were determined by HPLC-MS method. After liquidliquid extraction by ethyl acetate, the chromatographic separation was carried out on an Agilent ZORBAX SB-C18 (2.1 mm× 100 mm,3.5 μm) with a mobile phase consisting of methanol-0.1％ formic acid aqueous solution (30:70) . Mass spectrometry were performed in positive ion mode. Ion mass-to-charge ratio was set at 445 and 447 for mangiferin and, cefuroxime sodium (internal standard) respectivel for quantitive analysis. Results The main pharmacokinetic parameters of mangiferin form II, Ⅴ, Ⅵ were as follows: AUC(0-24 h) were (1323. 27 ± 218. 07) ,(1974. 34 ± 469. 24) ,(1737. 79 ± 623. 06) ng · mL-1 · h, respectively; Cmax were (321.92±85.18) ,(455.83±277.07) ,(319.92±86.07) μg·L-1, respectively; tmax were (0.70±0.45) , (0.50±0.32) ,(0.50± 0.34) h, respectively; t1/2z were (2.78± 1.72) ,(5.29± 2.67) ,(5.31± 2.82) h, respectively. Conclusion The main pharmacokinetic parameters of mangiferin polymorphs in plasma of rats are different, and mangiferin form Ⅴ has the hightest AUC(0-24 h) and Cmax.

Quantitative Detection for Polymorph of Levonorgestrel by Powder X-ray Diffraction / 医药导报

Objective According to the clinical medicinal crystal form———form γ of levonorgestrel, to establish the quantitative analysis method for levonorgestrel form γ by powder X-ray diffraction (PXRD) . Methods Firstly, single crystal X-ray diffractometry and powder X-ray diffractometry were used to confirm that the prepared levonorgestrel form γ was 100％ polymorphic purity, which provided a standard sample for quantitative analysis by single peak method; then, the standard samples of different quality levonorgestrel form γ for powder X-ray diffraction were weighed, the peak intensity values of characteristic diffraction peaks d = 6.4 , d = 6. 1  and d = 5. 6  of form γ as quantitative parameters selected, a linear relationship between the peak intensity value and the quality of form γ was established; finally, the content of levonorgestrel form γ was quantitatively analyzed. Results The peak intensity values of characteristic diffraction peaks d = 6.4 , d = 6.1  and d = 5.6  of levonorgestrel form γ and the quality showed a good linear relationship.In the range of form γ masses of 5 mg to 50 mg, the regression linear equations wereY = 459.59X+5 536.5, R2 = 0.993 0, Y = 430.03X+6 867.6, R2 = 0.990 5,Y = 615.95X+ 6 209.5, R2 = 0.990 8,respectively. Conclusion The method is simple, rapid, accurate and reliable, it can be used as quality control method for levonorgestrel polymorphs.

Physics, chemistry, and Hirshfeld surface analyses of gamma-irradiated thalidomide to evaluate behavior under sterilization doses / 药物分析学报

Thalidomide was indicated as a sedative and antiemetic and prescribed for pregnant women. Its tragic teratogenic effects culminated in withdrawal from the market. Since the discovery of its anti-angiogenic and anti-inflammatory actions, thalidomide has been used in the treatment of leprosy and multiple myeloma, which justify studies of its stability. We investigated the effects of irradiation of thalidomide up to 100 kGy (fourfold the usual sterilizing dose for pharmaceutics). The β polymorph of thalidomide was obtained in an isothermal experiment at 270 °C. All samples underwent gamma irradiation for specific times. At different doses, decomposition of the pharmaceutical was not observed up to 100 kGy. The observed effect was angle turning between the phthalimide and glutarimide rings modulated by repulsion towards the carbonyl group, leading to a stable energetic configuration, as measured by the equilibrium in the torsion angle after irra-diation. The thalidomide molecule has a center of symmetry, so a full turn starting from 57.3° will lead to an identical molecule. Further irradiation will start the process again. Samples irradiated at 30 and 100 kGy have more compact unit cells and a lower volume, which leads to an increase in the intermolecular hydrogen interaction within the unit cel , resulting in higher thermal stability for polymorph α.

Solubility and dissolution studies of tibolone polymorphs

ABSTRACT Different solid forms of an active pharmaceutical ingredient can have distinct chemical and physical characteristics. In this work, we studied the solubility and dissolution properties of the described tibolone polymorphic forms (I and II). Both forms were successively recrystallized and characterized by powder X-ray diffraction and attenuated total reflection infrared spectroscopy. Equilibrium solubility and dissolution profiles were performed for both forms. Solubility studies demonstrated that form II is statistically more soluble in water, 0.01 mol L-1 HCl and pH 4.5 acetate buffer. The solubility of forms I and II were explained in terms of crystal packing. Dissolution tests of tablets showed a lower release of polymorphic form II than form I from tablets. The results showed an impact of polymorphism on the quality of tibolone tablets and suggest that tibolone forms I and II can show distinct interactions with pharmaceutical excipients used in tablets. Therefore, only form I is acceptable for the preparation of tablet forms. Based on our results, we propose the quality control on tibolone raw materials using X-ray diffraction analysis and attenuated total reflection infrared spectroscopy.

Discussion on Polymorphs in the Consistency Assessment of Generic Drugs / 医药导报

This study discussed problems in consistency assessment of generic drugs and analyzed effect of polymorphs on drug quality and its influence on consistency of curative efficiency.Relationship between evaluation method of polymorphs and curative efficiency was investigated.It showed that establishment of curative efficiency related evaluation indicators was necessary and improvment of techniques was important.Drug quality criteria should be added with requirement of curative efficiency control.Related information based on polymorphs could be provided for technical research in consistency assessment.

The use of the software JST-XRD for identification of crystalline phases in pharmaceutical raw materials and tablets / Uso do software JST-XRD para identifcação de fases cristalinas em insumos farmacêuticos e medicamentos

Study of polymorphism is of great importance for the pharmaceutical industry once polymorphs may display different physicochemical properties, which, in turn, may result in stability differences that can bring problems for the manufacturing stages and the quality of fnal products. Although research on organic polymorphs has greatly increased in the last decades, it still does not cover all needs for the pharmaceutical market. Techniques such as spectroscopy in the infrared region, nuclear magnetic resonance, thermal analysis, X-ray diffraction, etc., can be used to identify polymorphism. The polymorphism is a property of the crystalline solid state, and can be evaluated by X-ray diffraction once each polymorph exhibits one specifc X-ray diffraction pattern. The JST-XRD program is a tool designed to help the identifcation of crystalline phases (including polymorphs) present in pharmaceutical ingredients and tablets by using X-ray diffraction data obtained from scientifc articles and patents. This paper presents new implementations for the JST-XRD and describes its use in the analysis of active pharmaceutical ingredient and marketed tablets of norfloxacin, mebendazole and atorvastatin calcium. By the means of comparison, JSTXRD allowed identifying the crystalline phases in the diffraction patterns of the analyzed drugs, showing the program suitability for polymorphism research, pre-formulation and quality control in pharmaceutical industries. JST-XRD can also be used for educational purposes in undergraduate and graduate programs in order to show the potentiality of X-ray powder diffraction in polymorphism analysis.(AU)

O estudo do polimorfsmo é de grande importância na indústria farmacêutica porque os polimorfos podem apresentar diferentes propriedades físico-químicas, podendo resultar em diferenças na estabilidade e desse modo causar problemas nas etapas de manufatura e no produto fnal. Embora a pesquisa de moléculas orgânicas que apresentam polimorfsmo tenha aumentado bastante nas últimas décadas, ainda não contempla todas as necessidades do mercado farmacêutico. Para a identifcação de polimorfsmo podem ser utilizadas técnicas como espectroscopia na região do infravermelho, ressonância nuclear magnética, análise térmica (DSC), difração de raios X, etc. O polimorfsmo, por ser uma propriedade do estado sólido e cristalino, pode ser avaliado através da difração de raios X, já que cada polimorfo apresenta um padrão de difração de raios X único. O programa JST-XRD é uma ferramenta projetada para auxiliar a identifcação de fases cristalinas, incluindo polimorfos, presentes em insumos farmacêuticos e comprimidos, usando dados de difração de raios X obtidos em artigos científcos e patentes. Esse trabalho apresenta novas implementações no JST-XRD e descreve seu uso na análise de amostras de princípio ativo e comprimidos comerciais de norfloxacino, mebendazol e atorvastatina cálcica. Através das comparações realizadas, JSTXRD permitiu identifcar todas as fases cristalinas dos difratogramas dos fármacos analisados, mostrando que o programa é adequado para pesquisa em polimorfsmo; na pré-formulação e controle de qualidade em indústrias farmacêuticas, assim como para uso didático em cursos de graduação e pós-graduação a fm de mostrar as potencialidades da difração de raios X na análise de polimorfsmo.(AU)

Analysis of the polymorphs of carbamazepin tablets by laser confocal micro-Raman spectrometer and establishment of the identification test model / 中国药学杂志

OBJECTIVE: To analyze the polymorphs of carbamazepin tablets by laser confocal micro-Raman spectrometer and establish the identification test model. METHODS: Reference Raman spectra of the four crystal forms of carbamazepin were established; then the polymorphs of the carbamazepin tablets from different manufacturers were analyzed, and an identification test model was established to distinguish the unknown samples. RESULTS: According to the results of the cluster analysis, the four batches of carbamazepin tablets from domestic manufacturers belonged to crystal form III. A qualitative model was created by choosing the first derivative and vector normalization method to process the spectra, using the factorization method to calculate, and selecting the 200-500, 650-850, 1 000-1 100, 1 500-1 700 cm-1 regions to compare. This model was verified to have high sensitivity, specificity, precisicion, negative prediction ability, and detection efficiency. CONCLUSION: The laser confocal micro-Raman spectrometer canbe used to analyze the polymorphs of carbamazepin tablets and the qualitative identification is rapid and accurate.

Study on Pharmacokinetics of Levofloxacin Polymorphs in Rats / 医药导报

Objective To study the pharmacokinetics difference of levofloxacin polymorphs in rats, evaluate the advantageous medical polymorph,and explore the effects of different polymorphs on clinical medicine. Methods Four crystal forms of levofloxacin were administered intragastrically to rats,and high performance liquid chromatography( HPLC)was used to measure the contents of levofloxacin in rat plasma. The pharmacokinetic parameters were calculated and compared Results After a single oral dose,the peak plasma concentration(Cmax)of crystal forms ofⅠ,Ⅱ,ⅢandⅣof levofloxacin was 6. 984,9. 692,9. 405,6.424 mg·L-1;the time to peak(tmax)was 0.6,0.9,1.0,1.0 h;the half-life(t1/2)was 4.207,2.97,4.857,1.695 h;theareaunderthecurve(AUC0→12h)was31.478,42.385,32.406,31.636mg·h·L-1. Conclusion Thereisnostatistically significant difference in pharmacokinetic parameters. However,compared with other crystal forms,plasma concentration of crystal form II is higher and maintained longer. Therefore,crystal form II of levofloxacin is an advantageous polymorph for medicine.

O patenteamento de polimorfos na indústria farmacêutica e o acesso a medicamentos / The patenting of polymorphs in the pharmaceutical industry and access to medicines

Recentemente, as discussões sobre o patenteamento na área farmacêutica e seu impacto sobre o acesso da população aos medicamentos tem se intensificado, e, em 2008, o GIPI decidiu que patentes incrementais não deveriam ser concedidas no Brasil. Assim, neste trabalho, são discutidos os possíveis impactos dessas patentes para o acesso aos medicamentos, por meio do estudo do caso dos polimorfos. Como contribuição, a importância do patenteamento de polimorfos nas várias áreas tecnológicas foi estimada a partir dos depósitos no Brasil. Foi observado que mais de 70 por cento dos depósitos são da área farmacêutica. Estudos de casos foram feitos com dois fármacos: paroxetina e atorvastatina. A detentora do medicamento referência depositou cerca de metade dos pedidos para polimorfos da paroxetina. No caso da atorvastatina, embora a detentora do registro não seja o maior depositante, é ela quem reivindica o maior percentual de polimorfos. O estudo constatou que a indústria farmacêutica tem usado agressivamente as patentes como estratégia econômica, confirmando a preocupação do setor saúde sobre o acesso aos medicamentos.

Recently, discussions on patenting in the pharmaceutical area and its impact on people's access to drugs have intensified, and in 2008 the GIPI decided that the incremental patents should not be granted in Brazil. So this paper discusses the possible impacts of these patents on access to medicines through the case study of the polymorphs. As a contribution, the importance of patenting of polymorphs in various technology areas was estimated from the deposits in Brazil. It was observed that more than 70 percent of deposits are in the pharmaceutical area. Case studies were made with two drugs: atorvastatin and paroxetine. The holder of the reference drug deposited about half of the requests for polymorphs of paroxetine. In the case of atorvastatin, although the holder of the registration is not the largest depositor, who claims it is the highest percentage of polymorphs. The study found that the pharmaceutical industry has aggressively used patents as economic strategy, confirming the concern of the health sector on access to medicines.