Chinese Journal of Pharmaceuticals

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Perspectives & Review

Progress in the Synthesis of Ozanimod Hydrochloride

WANG Junzheng, WANG Dongmei, YANG Tianming

2023, 54(08): 1145-1156. https://doi.org/10.16522/j.cnki.cjph.2023.08.001

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Ozanimod hydrochloride, a new type of oral sphingosine 1-phosphate(S1P) receptor modulator, is clinically used for the treatment of relapsing multiple sclerosis. In this review, the synthetic methods of ozanimod hydrochloride and its key intermediates are summarized and evaluated based on different schemes described in the literature. The scaffold structure of ozanimod hydrochloride is (S)-1-amino-4-(1,2,4-oxadiazol-3-yl)-2,3-dihydro- 1H-indene. Starting from 4-cyano-2,3-dihydro-1H-inden-1-one(2), chiral auxiliary agents or catalysts for asymmetric hydrogenation are used to construct the chiral amino group at the 1-position of 2,3-dihydro-1H-indene. Alternatively, the 1-carbonyl group is converted to the chiral hydroxyl before constructing the chiral amino group. The oxadiazole ring at the 4-position of 2,3-dihydro-1H-indene is synthesized in situ from 4-cyano group.

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Perspectives & Review

A review on Influencing Factors and Mechanisms of Tablet Disintegration

LI Wanting, SU Junhui, WANG Yawen, ZHAO Xiaoqing, XU Bing

2023, 54(08): 1157-1165. https://doi.org/10.16522/j.cnki.cjph.2023.08.002

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This paper summarizes the relevant literature on tablet disintegration published at home and abroad from 2010 to 2021, and outlines the influencing factors and possible disintegration mechanisms of tablet disintegration process. The disintegration of tablets is affected by the properties of raw and auxiliary materials, formulation composition, process parameters and disintegration medium. The mechanisms of tablet disintegration mainly include swelling, shape recovery and wicking. Among the commonly used functional auxiliary materials for disintegration, starch and its derivatives, croscarmellose sodium and sodium carboxymethyl starch promote disintegration through swelling. The mechanism of polyvinylpolypyrrolidone promoting disintegration is shape recovery. Cellulose and its derivatives promote disintegration through strong wicking effect. Future research directions include: correlation modeling between critical material attributes, critical process parameters and tablet disintegration behavior in tablet technology; objective, visual and quantitative characterization of tablet disintegration process and behavior; development and application of new pharmaceutical excipients to promote tablet disintegration.

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Perspectives & Review

Research Progress of Methods for Increasing Drug Loading of Dissolving Microneedles

RUAN Xi, ZHAO Feng, MA Yinling, YANG Xiaoting, PAN Zhenhua

2023, 54(08): 1166-1173. https://doi.org/10.16522/j.cnki.cjph.2023.08.003

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Dissolving microneedles can deliver drugs directly to subcutaneous lesions with a high drugdelivering capacity by painlessly inserted into the skin. However, due to the limitation of drug loading, their application in clinics has been limited. Therefore, improving the drug loading of microneedles is crucial for the application of dissolving microneedles. This paper reviews three strategies to improve the drug loading of microneedles, namely design of new formulation forms, improvement of microneedle structure and the preparation process of microneedles, hoping to provide a reference for the clinical translational research of microneedles.

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Perspectives & Review

Progress of On-line Monitoring Technologies and Process Simulation of Drug Coating

ZHANG Ran, LI Meng, YU Weiyong, WANG Xuezhong, WU Tao

2023, 54(08): 1174-1181. https://doi.org/10.16522/j.cnki.cjph.2023.08.004

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Coating is one of the key steps in preparation of pharmaceutical solid products, which plays an important role in improving the stability and modifying the release property. In this review, the principles, characteristics, and applications of various process analysis technologies(such as Raman spectroscopy, near-infrared spectroscopy, and terahertz pulse imaging) used to real-time and on-line analyze the critical attributes(such as thickness, weight gain and uniformity of coating layers) of products are summarized. Methods, modeling, and applications of process simulation of drug coating process are also reviewed, in order to elucidate the relationship between coating uniformity and process parameters, as well as process mechanisms. Finally, the development directions of process optimization are put forward, hoping to accelerate the automation and intelligence of drug coating process.

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Study on Refining Process and Impurities of Tofacitinib Citrate

XIE Fujia, FANG Zhijie, ZHOU Zhihui, FENG Lingling, LU Jun

2023, 54(08): 1182-1186. https://doi.org/10.16522/j.cnki.cjph.2023.08.005

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In this study, an improved refining process of tofacitinib citrate was reported, and the critical related substances were analyzed and controlled. Tofacitinib was purified in the acetonitrile-water mixed solvent, and the purity of the product was greater than 99.0％. Tofacitinib citrate was recrystallized in water, and the product purity was greater than 99.9％, with maximum single impurity less than 0.05％. The critical related substances of K, U, V and R(detected in the crude product and reference preparation) were synthesized, and their structures were confirmed by 1H NMR, 13C NMR and ESI-MS.

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Improved Synthetic Process of the Chrial Intermediate of Nirmatrelvir

DONG Mingming, TANG Jiawei, CHEN Shaoxin, ZHANG Fuli, WANG Jianbo, YU Jun

2023, 54(08): 1187-1192. https://doi.org/10.16522/j.cnki.cjph.2023.08.006

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In this paper, the synthesis process of a key chrial intermediate of nirmatrelvir, named methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate(1) hydrochloride was improved. Compound 6,6-dimethyl-3-oxobicyclo[3.1.0]hexane-2,4-dione(2) was used as the starting material to synthesize 6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2,4-dione(9) by ammoniation with urea. Compound 6,6-dimethyl-3-azabicyclo[3.1.0]- hexane(5) was synthesized from 9 by reduction. Compound (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexene(6) was stereoselectively synthesized from 5 via oxidation by the engineered bacteria containing monoamine oxidase AtMAON-M12. Compound 1 hydrochloride was obtained from 6 with purity of 99.9％ and enantiomeric excess up to 99.9％ by addition, cyanidation, Pinner reaction and salification, while the total yield reached 60.5％. The single enantiomer 6 was obtained by using monoamine oxidase AtMAON-M12 without resolution, which conformed to the green chemistry principle of atom economy.

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Improved Synthetic Process of the Key Intermediate of Rolapitant

QIN Ruosong, XIAO Guorong, ZHANG Liandi

2023, 54(08): 1193-1197. https://doi.org/10.16522/j.cnki.cjph.2023.08.007

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Benzyl (2R,4S)-5-oxo-2,4-diphenyloxazolidine-3-carboxylate(3) was obtained from N-carbobenzoxy-L-phenylglycine(2) by substitution with benzadehyde dimethyl acetal. In this reaction, acetonitrile was used as the reaction solvent instead of di-isopropyl ether in the original literature, which greatly simplified the operation and shortened the reaction time. Benzyl (2R,4S)-4-[[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]- 5-hydroxy-2,4-diphenyloxazolidine-3-carboxylate(5) was generated by substitution and reduction of compound 3. Compound 5, without hydrolysis, reacted directly with methyl bromide triphenylphosphine salt(Ylide reagent) in the "one pot" Wittig reaction to generate benzyl [(S)-1-[(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-2-phenylbut-3-en- 2-yl]carbamate(7). This reaction increased the yield from 54％ to 90％, and shorted the reaction time from 24 h to 6 h. After amino deprotection and salt production, the key intermediate of rolapitant, (S)-1-[(R)-1-[3,5-bis(trifluoromethyl)- phenyl]ethoxy]-2-phenylbutyl-3-en-2-amine maleate(1) was obtained with the overall yield of 59％ and the purity of 99.8％. The improved process was more suitable for industrial application.

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Improvement of Synthetic Process of 1α-Hydroxycholesterol

ZHANG Kesheng, GE Huantian, SUN Bin, JIN Can

2023, 54(08): 1198-1201. https://doi.org/10.16522/j.cnki.cjph.2023.08.008

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An improved synthetic process of 1α-hydroxycholesterol(1), a key intermediate of 1α- hydroxyvitamin D3, was reported by using cholesterol as raw material(2) through five steps, including oxidative dehydrogenation, epoxidation, selective ring opening, isomerization and reduction. Compared with the existed preparation process of 1, on the one hand, this route featured simple operation and mild conditions, avoiding the harsh conditions of liquid ammonia/lithium reduction at ﹣78 ℃. On the other hand, the ring-opening of 1α,2α-epoxy-4,6-cholestadiene- 3-one(4) was carried out by using phenylselenol, and the isomerization of ketene to enol ester was achieved by I2/ isopropylacetate system. After the optimization, the total yield for synthesis of 1 was 40％ with purity of 98％.

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Synthesis of the Related Substances of Rosuvastatin Calcium

QIU Hao, QIU Shoushuai, WANG Yiwen, CHEN Ranzhang, CHENG Qingfang

2023, 54(08): 1202-1207. https://doi.org/10.16522/j.cnki.cjph.2023.08.009

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In order to control the quality of rosuvastatin calcium, five related substances of rosuvastatin calcium were synthesized: [(3R,5S,E)-7-[4-(4-fluorophenyl)-2-[[2-[4-(4-fluorophenyl)-6-isopropyl-2-[Nmethyl( methanesulfonamido)]pyrimidin-5-yl]-2-hydroxyethyl]-N-methylsulfonamido]-6-isopropylpyrimidin-5-yl]- 3,5-dihydroxyhept-6-enoate] calcium salt(related substance A), [(3R,5S,E)-7-[4-(4-fluorophenyl)-2-[[(E)-2-[4- (4-fluorophenyl)-6-isopropyl-2-[N-methyl(methanesulfonamido)]pyrimidine-5-yl]vinyl]-N-methylsulfonamide]- 6-isopropylpyrimidin-5-yl]-3,5-dihydroxyheptyl-6-enoate] calcium salt(related substance B), N-[4-(4- fluorophenyl)-5-[(E)-2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]vinyl]-6-isopropylpyrimidin-2-yl]-Nmethylmethanesulfonamide( related substance C), N-[(R)-8-fluoro-6-[(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2- yl]-4-isopropyl-5,6-dihydrobenzo[h]quinazolin-2-yl]-N-methylmethanesulfonamide(related substance D), and N-[(S)- 8-fluoro-6-[(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]-4-isopropyl-5,6-dihydrobenzo[h]quinazolin-2-yl]-Nmethylmethanesulfonamide( related substance E). And their structures were confirmed by MS, 1H NMR and the optical rotation.

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Strain Breeding and Fermentation Process Optimization for Production of Polymyxin B by Paenibacillus polymyxa

LI Conghui, LI Zhenxin, ZHANG Zhengyu, YANG Songbai, YI Dong, CHEN Shaoxin

2023, 54(08): 1208-1215. https://doi.org/10.16522/j.cnki.cjph.2023.08.010

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Polymyxin B(1), a basic polypeptide antibacterial drug, was mainly produced by Paenibacillus polymyxa and showed significant effects on treatment of drug-resistant bacterial infections. The main components of 1 include B1, B2, B3, and B1-I. To increase the yield of 1, this study with P. polymyxa SIPI PB-1[fermentation unit: (837±50)mg/L] as the starting strain, obtained the mutant strain SIPI PB-N14[fermentation unit:(1 297±60)mg/L] through traditional mutagenesis and selection. Then, the fermentation medium and fermentation process of SIPI PB-N14 were optimized. Under the optimized fermentation conditions, the fermentation yield of 1 in a 5 L fermenter could reach (1 681±25)mg/L, of which the proportions of B1, B2, B3, and B1-I were (74.5±1.1)％, (20.4±0.8)％, (1.3±0.3)％, and (3.0±0.1)％, which met the requirements of API components and provided test data for industrial production.

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Preparation and in vitro-in vivo Evaluation of Azithromycin Dry Suspension

SHI Hongjuan, OUYANG Xu, WANG Ruiqiang, WANG Zhongyan

2023, 54(08): 1216-1223. https://doi.org/10.16522/j.cnki.cjph.2023.08.011

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This study developed the formulation and preparation of azithromycin(1) dry suspension based on the concept of quality by design(QbD). First, 1 and trisodium phosphate were granulated to improve the taste, then 1 particles and sucrose(grinding) were granulated, followed by mixing with the added sucrose. The second-step granulation and mixing process were optimized by Box-Behnken design with granulation time, adding sucrose ratio after granulation, and mixing time as independent variables and content uniformity as the dependent variable. The optimal process was as follows: granule time was 14 min, adding sucrose ratio was 40％, and mixing time was 44 min. Three batches of process validation samples prepared according to the optimized parameters had an average content uniformity of 2.3. And the dissolution behaviors of self-made preparations(T) and reference preparations(R) were similar in media with pH values of 2.0, 4.5, and 6.0. The bioequivalence between T and R was studied through a three-cycle partially repeated crossover design in healthy volunteers. The results showed that under fasting conditions, the cmax of T and R were 114.675 and 114.917 ng/mL, the AUC0→t were 552.41 and 594.87 h·ng·mL–1; under fed conditons, the cmax of T and R were 37.755 and 32.945 ng/mL, the AUC0→t were 276.66 and 257.87 h·ng·mL–1. The statistical analysis results of reference-scaled average bioequivalence(RSABE) or average bioequivalence(ABE) showed that T and R were bioequivalent. The quality and efficacy of the 1 dry suspension prepared in this study were consistent with the reference.

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Preparation of Borneol-modified Carbamazepine-loaded PLGA Nanoparticles and Their Tissue Distribution in Mice

REN Jungang, XU Ke

2023, 54(08): 1224-1232. https://doi.org/10.16522/j.cnki.cjph.2023.08.012

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In this study, borneol-modified carbamazepine(1) nanoparticles were prepared by solvent diffusion method using PLGA as carrier material, and their tissue distribution in mice was investigated. First, the formulation was optimized by Box-Behnken design combined with response surface methodology with poloxamer 188 concentration, PLGA amount, the volume ratio of oil-to-water, and mass ratio of drug-to-lipid as the independent variables, and the entrapment efficiency and particle size as the dependent variables. The in vitro characterization results showed that the average particle size of the borneol-modified 1 nanoparticles prepared by the optimized formnlation was 90 – 100 nm, the entrapment efficiency and drug loading were about 72％ and 6.7％. After tail intravenous administration of the selfmade borneol-modified 1 nanoparticles to mice, the distribution behavior, especially the brain targeting of 1 in mice was investigated. The results showed that borneol-modified 1 nanoparticles could significantly extend the average residence time in mice, and borneol could promote the transport of 1 nanoparticles across the blood-brain barrier. The results indicated that the borneol-modified 1 nanoparticles had the potential to treat epilepsy.

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Investigation on the Lyophilization Technology of Cabazitaxel Nanoliposomes

LIU Yuhong, JIANG Yu, HAO Guizhou, LIU Shankui

2023, 54(08): 1233-1240. https://doi.org/10.16522/j.cnki.cjph.2023.08.013

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In order to improve storage stability and reduce residual ethanol, cabazitaxel nanoliposomes were prepared into lyophilized injection, and the lyophilization process was investigated and optimized. Taking the appearance, main drug content, encapsulation efficiency, moisture content, residual ethanol and the storage stability of lyophilized powder as evaluation indicators, the effects of dosage of lyophilized protective agent(sucrose), the filling volume of feed liquid, pre-freezing speed and drying temperature on the quality of the lyophilized injection were investigated. The results showed that the optimum mass ratio of sucrose to phospholipid was 5.0; the mass concentration of cabazitaxel in the nanoliposomes was 2 mg/mL; specification was 20 mg per bottle; xilin bottle specification was 20 or 30 mL. The optimal lyophilization process parameters were as follows: the pre-freezing temperature was –40 ℃, the shelf cooling time was 90 min, then holding at –40 ℃ for 5 h; the primary drying was conducted at –15 ℃ for 14 h; the secondary drying was conducted at 28 ℃ for 28 h; the total lyophilization time was 48.83 h; a stepwise heating mode was adopted in the whole drying process. The lyophilization cycle of optimal process was greatly shortened, and the obtained lyophilized injection had good storage stability.

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Optimization of Extraction Process for Tangerine Peel Formula Granules

LI Taomin, PENG Banggui, ZHANG Lanlan, HE Rongrong, LIU Liaoyuan

2023, 54(08): 1241-1246. https://doi.org/10.16522/j.cnki.cjph.2023.08.014

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A three-factor and three-level experiment was conducted with decoction time, adding amount of water and decocting times as the independent variables by Box-Behnken design combined with response surface methodology. The weights for evaluating indexes, namely the extraction yield and the contents of narirutin, hesperidin, nobiletin and tangeretin were calculated by analytic hierarchy process(AHP), entropy weight method and the combination of AHP and entropy weight method, respectively. Then, the comprehensive score of the above 5 indicators was used as the evaluation index to optimize the extraction process parameters of tangerine peel formula granules. The results showed that the optimized extraction process parameters were as follows: adding 14 times of the amount of water, decocting 3 times, and 60 min per extraction. The results of verification test showed that the extraction process was stable, simple and feasible, which could provide a reference for the preparation process study of tangerine peel formula granules.

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Preparation and Quality Evaluation of Suoluozi Enteric-coated Pellet-based Capsules

YIN Wenjia, HUANG Lihua, XIONG Fuliang, ZHANG Ming, SHI Chuan

2023, 54(08): 1247-1253. https://doi.org/10.16522/j.cnki.cjph.2023.08.015

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The sucrose pill cores were sequentially coated with a drug layer, an isolation layer, and an enteric layer to prepare the enteric-coated pellets loaded with escin from Suoluozi(Semen Aesculi) by bottom spray coating in a fluidized bed. A single factor test combined with a multi-index comprehensive evaluation method was adopted to optimize the formulation of enteric-coated pellets with the drug loading rate, yield, process feasibility, total escin content, and release amount within 2 h in acidic media as the evaluation indicators. Three batches of Suoluozi enteric-coated pellets were prepared according to the optimal formulation. The average particle size, bulk density, friability and total escin content of the enteric-coated pellets were 665.26 μm, 0.92 g/mL, below 2.5％, and (101.30±0.79)％, respectively. After filling the obtained enteric-coated pellets into the capsules, an in vitro release test was carried out. The results showed that the release amount of enteric-coated pellet-based capsules within 2 h in acidic media was (5.26±2.25)％, but the drug was basically completely released in phosphate buffer(pH 6.8) in 45 min.

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Formulation Optimization and Preliminary Quality Evaluation of Rufinamide Tablets

DING Yinchun, TANG Jihui

2023, 54(08): 1254-1258. https://doi.org/10.16522/j.cnki.cjph.2023.08.016

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The formulation of rufinamide(1) tablets were optimized in this paper. The release curves of 1 tablets in 0.1 mol/L hydrochloric acid and phosphate buffer(pH 6.8) were drawn. The parameters, namely the proportion of filling agent, adhesive agent amount and type, and disintegrating agent amount, were optimized by evaluating the similarity of release curves between the self-made tablets and the reference preparation. The results showed that the optimized composition of a tablet was 200.00 mg of 1, 50.00 mg of lactose, 66.75 mg of microcrystalline cellulose PH101, 20.00 mg of corn starch, 6.50 mg of HPMC K4M, and 10.00 mg of cross-linked sodium carboxymethyl cellulose. The release test results showed that the release curves between the optimized self-made tablets and the reference preparation were similar. In addition, the optimal tablets produced in a pilot-scale was rather stable within 6 months.

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Pharmaceutical Management & Information

Implications of the EMA-FDA Parallel Scientific Advice for China Communication System

ZHANG Siyao, LIANG Yi

2023, 54(08): 1259-1264. https://doi.org/10.16522/j.cnki.cjph.2023.08.017

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Pharmaceutical Management & Information

General Considerations for Pharmaceutical Research on Generic Injectable Microspheres of Chemical Drugs

NA Xinzhu, ZHANG Junlin, HU Yuxi

2023, 54(08): 1265-1268. https://doi.org/10.16522/j.cnki.cjph.2023.08.018

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Pharmaceutical Management & Information

Implementation and Optimization of the Policy of Encouraging R&D and Declaring the Medicine List for Children in China

WANG Qian, YANG Haoyu, JIANG Feng, WANG Shengming, TIAN Kan, XIE Shiyu

2023, 54(08): 1269-1272. https://doi.org/10.16522/j.cnki.cjph.2023.08.019

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Pharmaceutical Management & Information

Visual Analysis of Generic Drug Substitution Policy Research

WU Yi, HE Jingwen, JIANG Rong, SHAO Rong

2023, 54(08): 1273-1277. https://doi.org/10.16522/j.cnki.cjph.2023.08.020

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