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In this paper, 50 batches of representative traditional Chinese medicine tablets were selected and the disintegration time was examined with the method in Chinese Pharmacopoeia. The disintegration time and disintegration phenomenon were recorded, and the dissolution behaviors of water-soluble and ultraviolet-absorbent components during the disintegration process of tablets were characterized by self-control method. The results revealed that coating type and raw material type influenced the disintegration time of tablets. It was found that only 4% of traditional Chinese medicine tablets had obvious fragmentation during the disintegration process, while 96% of traditional Chinese medicine tablets showed gradual dissolution or dispersion. Furthermore, according to the disintegration speed, disintegration phenomenon, and whether the cumulative dissolution of measured components was > 90% at complete disintegration, a disintegration behavior classification system(DBCS) was created for the regular-release traditional Chinese medicine tablets. As a result, the disintegration behaviors of 50 batches of traditional Chinese medicine tablets were classified into four categories, i.e. ⅠA_2, ⅠB_1, ⅡB_1, and ⅡB_2. traditional Chinese medicine tablets(Class I) with disintegration time ≤ 30 min were defined to be rapid in disintegration, which can be the objective of optimization or improvement of Chinese herbal extract(semi extract) tablets. Different drug release models were used to fit the dissolution curve of traditional Chinese medicine tablets with gradual dissolution or dispersion phenomenon(i.e. Type B tablets). The results showed that the dissolution curves of water-soluble components in the disintegration process conformed to the zero order kinetics and the Ritger-Peppas model. It could be inferred that the disintegration mechanisms of type B tablets were a combination of dissolution controlled and swelling controlled mechanisms. This study contributes to understanding the disintegration behavior of traditional Chinese medicine tablets, and provides a reference for the design and improvement of disintegration performance of traditional Chinese medicine tablets.
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Commerce , Medicine, Chinese Traditional , Tablets , Water , Drug CompoundingABSTRACT
To explore the quality consistency evaluation method for multi-component traditional Chinese medicine and establish a dissolution evaluation method suitable for the characteristics of multi-component Chinese patent medicine, this study discussed the characteristics and advantages of the flow-through cell method in the dissolution evaluation of Chinese patent medicine by comparing the impact of the small cup method and the flow-through cell method on the dissolution behavior of water-soluble and lipid-soluble major active components of Danshen Tablets. Dissolution tests were performed using the small cup method as described in the 2020 edition of the Chinese Pharmacopoeia and the newly introduced flow-through cell method(closed-loop method) with water solution containing 0.5% SDS as dissolution medium. Cumulative dissolution curves of the water-soluble component salvianolic acid B and the lipid-soluble component tanshinone Ⅱ_A in Danshen Tablets were plotted, and fitting and similarity analysis of the dissolution models was conducted to identify the characteristics and advantages of the flow-through cell method. For the small cup method, 150 mL of water containing 0.5% SDS was used as the dissolution medium, with a rotation speed of 75 r·min~(-1) and a temperature of(37±0.5) ℃, and 3 mL of samples were taken at 15, 30 min, 1, 2, and 4 h, with fresh dissolution medium added at the same temperature and volume. For the flow-through cell method, a closed-loop system was used. Danshen Tablets were placed in the flow-through cell with approximately 6.7 g of glass beads, and 150 mL of water containing 0.5% SDS was used as the dissolution medium. The flow rate was set at 20 mL·min~(-1), and the temperature and sampling were the same as the small cup method. The results showed that compared with the small cup method, the flow-through cell method had stronger discriminative power and higher sensitivity in distinguishing the dissolution behavior of the two components, and could better reflect the differences in formulation quality, especially for water-insoluble lipid-soluble components. Given that there were no essential differences in the in vitro release kinetics between the two methods, the flow-through cell method could not only replace the traditional small cup method but also better guide the formulation development and identify quality issues of formulations.
Subject(s)
Salvia miltiorrhiza , Medicine, Chinese Traditional , Tablets , Water , Lipids , SolubilityABSTRACT
Based on the "requirements on the submitted documents for consistency evaluation of generic oral solid dosage forms of chemical drugs" and relevant guidance, this article summarized and formulated the decision tree of in vitro consistency evaluation of oral solid generic drugs, discussed the differences and common problems of in vitro evaluation research projects under different conditions, selective analyzed the technical requirements and concern problems of unconventional research projects, and proposed corresponding recommendations for concern problems, in order to provide more references for the follow-up study on consistency evaluation of oral solid generic drugs.
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OBJECTIVE：To investigate the in vitro quality consistency of domestic Nitroglycerin table t imitative preparation and reference preparation （original drug ）. METHODS ：The contents of nitroglycerin and related substances in 1 batch of Nitroglycerin tablet reference preparation （manufacturer A ）and 4 batches of imitative preparation （manufacturer B ，C，D，E） were determined according to Nitroglycerin Tablet Import Drugs Registration Standard JX 20010267. The paddle method of dissolution determination method was adopted ，with the rotating speed of 50 r/min. HPLC method was adopted to determine the dissolution amount of 5 batches of above preparations in 4 kinds of dissolution mediums （pH 1.2 hydrochloric acid solution ，pH 4.0 acetate buffer solution ，pH 6.8 phosphate buffer solution ，water） within 10 min.The accumulative dissolution rate was calculated，and dissolution curves of samples were drawn.The similarity of the dissolution curves was evaluated by calculating similarity factor （f2）of 2，5，8 min accumulative dissolution rate. RESULTS ：The contents of nitroglycerin in the preparations from manufacturer A ，B，C，D，E were 99.8％，98.3％，94.0％，93.3％，96.7％，respectively（n＝2）；the contents of related substance were 0.46％，0.55％，0.63％，0.72％，0.49％，respectively（n＝2）. Using reference preparation of manufacturer A as control，f2 of imitative preparation from manufacturer B ，C，D，E were 74，28，25，67 in pH 1.2 hydrochloric acid solution ；76， 26，28，84 in pH 4.0 acetate buffer solution ；79，39，35，71 in pH 6.8 phosphate buffer solution ；69，32，37，62 in water ， respectively. CONCLUSIONS ：The method is suitable for in vitro quality consistency evaluation of Nitroglycerin table timitative preparation. Compared with reference preparation ，the contents of main components in the imitative preparations from manufacturer C，D are lower ；in vitro dissolution curves of those imitative preparation are not similar to reference preparation .
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Objective: To establish a method for the determination of the particle size of nifedipine and study the effect of particle size on the in vitro dissolution behaviors of nifedipine sustained release tablets. Methods: Light scattering was used to study the parti-cle size of nifedipine API. Nifedipine APIs with different particle sizes were prepared by a portable high-speed grinder. The in vitro dis-solution curve of nifedipine sustained released tablets (Ⅰ) was determined by HPLC. The similarity was evaluated using the similarity factor ( f2) with the original drug (trade name: Adalat-L, specification: 10mg) as the reference preparation. Results: The granulo-metric conditions were as follows: the pump speed of laser size analyzer was 1 800 r·min-1, the shading rate was 8%-20% , the bal-ance time was 0 s, the media was 0. 3% Tween 80, and the ultrasonic time was 1 min. The in vitro dissolution of nifedipine sustained released tablets (Ⅰ) showed that the smaller particle size of nifedipine API, the better the dissolution was. As the Dv90 ( the particle size accounting for 90% of the total particle quantity) was reduced from 118. 781 μm to 3. 471 μm, the cumulative dissolution in 0. 25 h of nifedipine sustained released tablets (Ⅰ) increased from 11. 2% to 44. 0% , the similarity factor ( f2) compared with the dis-solution cruve of the original drug increased firstly and then decreased, and f2value was 77 when the Dv90 was 29. 823 μm. Conclu-sion: The in vitro dissolution of nifedipine sustained released tablets is improved remarkably by micronization technology. In order to produce nifedipine sustained released tablets (Ⅰ) with the same bioavailability as the original drug preparation, the particle size of nife-dipine API should be controlled within the range of 15 μm≤Dv90≤45 μm.
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OBJECTIVE: To explore the similarity of the dissolution curves of self-made and original telmisartan /hydrochlorothiazide tablets and provide basis for the prescription and process screening of self-made preparation and the quality similarity evaluation with original preparation. METHODS: The dissolution curves of telmisartan and hydrochlorothiazide from self-made and original preparations in four different dissolution media were determined using HPLC. The HPLC method was performed on Welch Ultimate XB-C8 column (4.6 mm × 250 mm, 5 μm) with mobile phase A consisting of ammonium dihydrogen phosphate solution (2.0 g ammonium dihydrogen phosphate was dissolved in 1 L water then adjusted to pH 3.0 with phosphoric acid) and mobile phase B consisting of acetonitrile- methanol (50:50) at a flow rate of 1.2 mL•min-1. The detection wavelength was set at 270 nm. The injection volume was 20 μL. Then f2 factor method was used to evaluate the similarity. RESULTS: The dissolution curves of self-made and original preparations of telmisartan /hydrochlorothiazide tablets in different dissolution media showed similarity, with the f2 factor ≥50 or the dissolution rate within 15 min≥85%. CONCLUSION: The dissolution behaviors of self-made and original telmisartan /hydrochlorothiazide tablets are basically similar, which indicates that the prescription and technology of self-made preparation are reasonable and feasible.
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OBJECTIVE: To investigate and compare the dissolution behaviors of diclofenac sodium enteric-coated tablets from Beijing Novartis, Turkey Novartis and German Novartis respectively. METHODS: According to the dissolution test METHODS: in Chinese Pharmacopoeia, the dissolution curves of the preparations in various media were investigated. Whether the dissolution stage in acidic medium has influence on the dissolution behavior as well as the influence of the ionic strength of buffer medium were investigated. RESULTS: The dissolution curves of diclofenac sodium enteric-coated tablets in media of pH 1.0, 5.5, 6.0 and 6.8 could be used as the characteristic dissolution curves of the preparation. The dissolution behaviors of the three preparations after being dissolved in acidic medium for 2 h were similar; the dissolution behaviors were quite different without the dissoulution stage in acid medium; the larger the ionic strength of the buffer medium was, the faster the dissolution rate of the enteric coated tablets was. CONCLUSION: The dissolution behavior of diclofenac sodium enteric-coated tablets depends on the dissolution rates of the enteric coating and the tablet core. The RSD of the dissolution rate just after the formulation starts to dissolute is large; the dissolution phase in acidic medium and the ionic strength of the buffer medium has influence on the dissolution behavior. There is difference in the in vitro dissolution behaviors of diclofenac sodium enteric-coated tablets from manufacturers in different areas of the same group. This study may provide data support for the selection of multi-source reference preparations in the evaluation of generic drug conformance, and plays an important role in guiding the prescription screening and bioequivalence risk assessment.
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OBJECTIVE: To compare the similarity of the dissolution curves of cloperastine hydrochloride tablets in four kinds of dissolution media to provide reference for evaluating the consistency of the quality of domestic generics and revising the drug standards. METHODS: The dissolution curves of home-made and original patented cloperastine hydrochloride tablets in hydrochloric acid solution (pH 1.2), disodium hydrogen phosphate and citric acid buffer solution (pH 4.0), phosphate buffer solution (pH 6.8) and water were determined and the similarity was evaluated according to the AV values. RESULTS: In the four kinds of media, the AV values were more than 15.0. CONCLUSION: The dissolution behaviors of home-made and original patented cloperastine hydrochloride tablets in the four kinds of media are dissimilar, which indicates that the domestic generics urgently need to be improved in the prescription or the manufacturing process.
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OBJECTIVE: To establish a determination method of the dissolution curves of albendazole tablets with differentiation ability and investigate the similarity of dissolution curves in vitro between reference preparation and generic preparations.METHODS: Paddle method was adopted with rotation speed of 50 r•min-1 and the dissolution medium volume was 900 mL. The dissolution media were pH 1.2 hydrochloric acid solution and water. The similarity factor (f2) method was used to evaluate the comparability of dissolution curves.RESULTS: The three established dissolution curves had good distinguishing ability. As shown by the similarity factor (f2), the generic preparation from manufacture A was similar to the reference preparation, while those from the manufacture B and C were not similar.CONCLUSION: The study provides the experimental basis for the consistency evaluation of the dissolution curves of abendazole tablets.
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Objective To establish a method for determining the dissolution of isoniazid tablet in vitro and evaluate the dissolution profiles.Methods The paddle method was used for the dissolution test and the rotation rate was set at 50 r/min.The hydrochloric acid solution (pH 1.2),acetate buffer solution (pH 4.5),phosphate buffer solution (pH 6.8) and water (900 mL) were used as the dissolution media.HPLC was used for the determination of dissolution quantity.Results There was a good linear relationship between the quality concentration of i soniazid and peak area in the range of 0.1981-0.9904μg (r =0.9993).The average recovery was 100.2％.Precision,reproducibility,and specificity tests were good.Among the determination of 16 manufactures,the dissolution profiles in water of four manufactures were not similar with Sandoz reference preparation.Conclusion The HPLC method is simple.The accuracy and specificity of determination of isoniazid dissolution are improved.There is significant difference in the dissolution profiles between different manufactures.The method can be used for the determination of dissolution curves for isoniazid tablets.
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Objective:To compare the dissolution of compound fructus forsythiae, paracetamol and chlorphenamine maleate cap-sules from different manufacturers.Methods: The dissolution test was carried out by a basket method in 900 ml dissolution medium with the rotating speed at 100 r·min-1. The dissolution profiles of compound fructus forsythiae,paracetamol and chlorphenamine mal-eate capsules from different manufacturers in four dissolution media including hydrochloric acid solution, pH 4.5 acetate buffer solu-tion,water and pH 6.8 phosphate buffer solution were determined,and the dissolution curves were compared by a similar factor meth-od. Results:The cumulative dissolution of compound fructus forsythiae,paracetamol and chlorphenamine maleate capsules from seven manufacturers was all over 70% in 30 min in hydrochloric acid solution,while failed to dissolve well in pH 4.5 acetate buffer solution, water and pH 6.8 phosphate buffer solution. All the dissolution curves in the 4 dissolution media were different among the batches. Conclusion:The quality of compound fructus forsythiae,paracetamol and chlorphenamine maleate capsules from various manufacturers is much different. Promising dissolution should be guaranteed,at the same time,the stability needs to be improved.
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OBJECTIVE:To evaluate the dissolution curves similarity of generic and original preparation of Losartan potassium tablets,and to provide reference for improving quality evaluation of the preparation.METHODS:Using hydrochloric acid solution (pH 3.0),phosphate buffer solution(pH 4.5),phosphate buffer solution (pH 6.8) and water as medium,paddle method was adopted for dissolution test with dissolution medium volume of 900 mL and rotation speed of 50 r/min.UV-visible spectrophotometry was adopted to determine accumulative dissolution of generic and original preparation of Losartan potassium tablets with the detection wavelength of 256 um.The similarity of dissolution curves were evaluated by calculating similarity factor(f2).RESULTS:The linear range of losartan potassium was 12.11-35.96 μg/mL (r≥0.999 7).RSDs of precision,stability and reproducibility tests were all lower than 5.0％.The recoveries of 4 dissolution media were 98.66％-100.84％ (RSD=0.77％,n=9),98.91％-100.59％ (RSD=0.49％,n=9),98.33％-101.39％ (RSD=0.85％,n=9),99.46％-101.32％ (RSD=0.55％,n=9).In 4 dissolution media,f2 of the dissolution curves of 3 batches of generic and original preparation of Losartan potassium tablets were all higher than 70.CONCLUSIONS:The dissolution curves of self-made and original preparation of Losartan potassium tablets show good similarity.
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OBJECTIVE: To investigate the in-vitro release behavior of venetoclax preparations, the pharmacokinetic processes and the correlations between in-vitro release and in-vivo absorption of venetoclax in Beagle dogs. METHODS: The dissolution curves of venetoclax preparations in different dissolution media were studied. HPLC method was established for the determination of venetoclax in Beagle dogs, and the pharmacokinetics were studied for commercial venetoclax tablets in Beagle dogs under fed and fasted states.The IVIVC study was carried out by linear regression of cumulative in-vitro drug release and in-vivo absorption accumulation percentage data. RESULTS: The in-vitro release behavior among venetoclax formulation in 4 dissolution media were significant difference. The simple, accurate and rapid analysis method for venetoclax blood samples was established. The fed group and the fasted group AUC0→∞ were (32.38±5.87) and (27.70±6.32) mg·h·L-1, the concentration of peak were (4.04±0.78) and (3.72 ±0.69) μg·mL-1, the peak time were (6.01±1.04) and (4.27±0.92) h, respectively, and there was obvious difference (P<0.05) in AUC0→∞ and the peak time between two group. Percentage of in-vivo absorption was in good agreement with in-vitro release in pH 6.8 0.2%SDS media. CONCLUSION: The study shows that food could improve the bioavailability of venetoclax formulation; 0.2%SDS pH 6.8 media (paddle, 75 r·min-1) is the in-vivo release of venetoclax associated with the in-vitro release condition.
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OBJECTIVE: To establish a new dissolution method of Ligustrazine Phosphate Pills, which provides reference for revising the quality standard. METHODS: The dissolution media were hydrochloric acid solution(pH 1.2), acetate buffer solution(pH 4.5), phosphate buffer solution(pH 6.8) and water. The dissolution curves of six batches of Ligustrazine Phosphate Pills in the four kinds of dissolution media were compared to establish the dissolution method. Apparatus 2 was used for the new method of dissolution test, using 500 mL water as the dissolution medium, at the rate of 75 r·min-1. The dissolution solution was taken at 20 min and analyzed by HPLC. The dissolution limit was set at 80%. RESULTS: The dissolution curves of the six batches of samples were similar in the four kinds of dissolution media. The pills were dissolved completely within 15 min. CONCLUSION: The determination method is highly reproducible, accurate and reliable, which can objectively reflect the dissolution of ligustrazine phosphate pills, and provides a basis for the reasonable unification and revision of the dissolution test of the current quality standard.
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Objective To develop a formulation of generic Valsartan Tablets and evaluate the quality consistency in vitro.Methods Diovan(R)~ HCT (80 mg) was used as the reference drug.In order to determine the best formulation and the best preparation processing,the single factor experiments were applied to determining the best formulation and the best preparation processing.And dissolution test was used as the evaluation index in the single factor experiments.Meanwhile the dissolubility of generic Valsartan Tablets and original preparation was investigated in four different media to evaluate the similarity of dissolution by calculating similar factor (f2).Results The dissolution was above 85％ of three batches of generic Valsartan Tablets in the phosphate buffer (pH 6.8).The similar factors were all more than 50 in the water,hydrochloric acid solution (pH 1.2),and acetate buffer solution (pH 4.5).Conclusion The f2 similarity factor results indicate a similarity in the reference drug and generic Valsartan Tablets which were developed by single factor experiments,which means the quality of genetic Valsartan Tablets is qualified.
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Objective To evaluate the similarity of dissolution behavior in vitro of self-made and reference listed drug(RLD) of esomeprazole magnesium enteric tablets. Methods The dissolution test method and HPLC method were established according to Chinese pharmacopoeia. The HPLC method was validated according to ICH guidance. The dissolution behavior of the 3 batches of the self-made drug and RLD were compared in dissolution medium of pH 1.2 HCl solutuion,pH 4.5 phosphate buffer,pH 6.8 phosphate buffer,pH 1.2 HCl solutuion(2 h)and pH 6.0 phosphate buffer,pH 1.2 HCl solutuion(2 h)and pH 6.8 phosphate buffer,and puri?fied water with different rotation rates. Results The HPLC validation results for linearity,repeatability,recovery,etc. all met the re?quirement. The similarity factors F2 between the self-made drug and RLD were greater than 50 in different dissolution mediums. Con?clusion The dissolution behaviors of the self-made drug and RLD are similar.
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Objective To compare the dissolution behavior between domestic trepibutone tablets and original reference product, and provide a basis for evaluating the quality consistency of generic drugs. Methods Four dissolution media recommended by Japanese Orange Book and a domestic standard dissolution media were selected to determined the dissolution profile,and f2 factor was calculated to investigate the consistency of stripping curves. Results In water,pH 4.0 and pH 1.2,the f2 of domestic formulation and reference formulation was under 50,and the dissolution profile was inconsistent.Dissolution behavior of domestic preparations of different manufacturers was dissimilar.In water,the f2 of domestic preparations of different batches of the same manufacturer was over 99.9,and the dissolution behavior was similar. Conclusion The dissolution method of existing domestic standard can not distinguish the dissolution behavior of different products,and it should be revised and completed.There is still great difference in quality between the domestic preparations and reference preparations.
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OBJECTIVE:To establish a method for the dissolution determination of Dronedarone hydrochloride tablet,and eval-uate the quality consistency of its generic and original preparations. METHODS:UV spectrometry was performed on the column of 288 nm,dissolution media of Phosphate buffer solution (pH4.5),0.1 mol/L Hydrochloric acid solution [adding into 0.5% sodium dodecyl sulfate(SDS)],Phosphate buffer solution [pH6.8,adding into 0.5%SDS] and water,volume of dissolution medium was 1 000 ml,rotation speed was 75 r/min,the dissolution of generic and original preparations of Dronedarone hydrochloride tablet was detected,and the similarity of dissolution curve was evaluated by calculating the similarity factor (f2). RESULTS:The linear range of dronedarone hydrochloride was 2.147-25.764 μg/ml;RSDs of precision,stability and reproducibility tests were lower than 2.0%;recoveries 4 dissolution media were 99.53%-101.05%(RSD=0.48%,n=9),98.95%-100.05%(RSD=0.39%,n=9), 99.54%-100.20%(RSD=0.24%,n=9)and 98.54%-100.06%(RSD=0.44%,n=9). In the 4 dissolution media,f2 of the dissolu-tion curve of 3 batches of generic and original preparations of Dronedarone hydrochloride tablet was 56,60,63,68,68,52,59, 67,65,68,76,62,respectively. CONCLUSIONS:The method is suitable for the dissolution determination of Dronedarone hydro-chloride tablet;meanwhile,the in vitro dissolution curves of generic and original preparations of Dronedarone hydrochloride tablet show similarity,so the quality consistency is good.
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OBJECTIVE:To evaluate the similarity of in vitro dissolution of self-made and original preparation of Ramelteon tablet. METHODS:The paddle method was adopted with rotational speed of 50 r/min,using water,pH1.2 hydrochloric acid solu-tion,pH4.0 acetate buffer solution and pH6.8 phosphate buffer solution as dissolution media,HPLC was used to determine the cu-mulative dissolution of main components of self-made and original preparation of Ramelteon tablet at different time points,dissolu-tion profile was drew,then f2 was used to evaluate its similarity. RESULTS:In the 4 dissolution media,the f2 of self-made and original preparation of Ramelteon tablet was 62.8,80.0,77.7,76.2,respectively,which indicated that the dissolution profiles showed similarity. CONCLUSIONS:The established HPLC is suitable for the dissolution determination of Ramelteon tablet;the dissolution profiles of the self-made and original preparations are similar,it preliminary indicates the prescription and technological rationality of self-made preparation.
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Objective To evaluate the similarity of dissolution behavior in vitro of self-made and reference listed drug (RLD) of esomeprazole magnesium enteric tablets. Methods The dissolution test method and HPLC method were established according to Chinese pharmacopoeia. The HPLC method was validated according to ICH guidance. The dissolution behavior of the 3 batches of the self-made drug and RLD were compared in dissolution medium of pH 1.2 HCl solutuion, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer, pH 1.2 HCl solutuion (2 h) and pH 6.0 phosphate buffer, pH 1.2 HCl solutuion (2 h) and pH 6.8 phosphate buffer, and purified water with different rotation rates. Results The HPLC validation results for linearity, repeatability, recovery, etc. all met the requirement. The similarity factors F2 between the self-made drug and RLD were greater than 50 in different dissolution mediums. Conclusion The dissolution behaviors of the self-made drug and RLD are similar.