Effect of fill weight, capsule shell, and sinker design on the dissolution behavior of capsule formulations of a weak acid drug candidate BMS-309403

Two strengths of BMS-309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower-strength capsules exhibited slower dissolution than the higher-strength capsules filled with the same stock granulation. Higher variability was also observed for the lower-strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.     

Effect of Fill Weight,Capsule Shell,and Sinker Design on the Dissolution Behavior of Capsule Formulations of a Weak Acid Drug Candidate BMS‐309403

Two strengths of BMS‐309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower‐strength capsules exhibited slower dissolution than the higher‐strength capsules filled with the same stock granulation. Higher variability was also observed for the lower‐strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.     

3D Printing and Dissolution Testing of Novel Capsule Shells for Use in Delivering Acetaminophen

Individualized drug delivery improves drug efficacy and safety for patients. To implement individualized drug delivery, patient-specific tailored dosages produced on a small scale are needed. However, current pharmaceutical manufacturing is not suitable for personalized dosage forms. Although convenient to deliver various drugs, current gelatin capsules using animal collagen protein have many limitations, such as releasing drugs too fast and incompatibility with some diets. In contrast, 3D printed capsules have great potential to advance individualized treatments. In this paper, we 3D printed and tested non-animal-based capsule shells for the delivery of acetaminophen. Capsule shells were composed of poly(vinyl) alcohol (PVA) and PVA blends with 5-25% hydroxypropyl methylcellulose (HPMC). Dissolution of acetaminophen when delivered in –hese capsule shells was tested using a USP dissolution test apparatus 2 (paddle type) at gastric pH. The novel shells were compared to each other and to commercially available hard gelatin capsules. Dissolution results show that acetaminophen when delivered in 3D printed capsules was slower than when delivered by gelatin capsules. Increasing the percentage of HPMC in the blend further delayed its release and dissolution. This delay could potentially increase the efficacy and reduce the side effects of acetaminophen. These shells also offer a non-animal-based alternative to gelatin capsules. Furthermore, 3D printing of capsule shells with specific polymer blends may be useful for patient-specific therapy in compounding pharmacies across the country.     

Surfactant-Mediated Dissolution of Metformin Hydrochloride Tablets: Wetting Effects Versus Ion Pairs Diffusivity

The aqueous solubility of metformin (pKa: 2.8 and 11.5) in the pH range of 1.2–6.8 is 300 mg/mL. Thus, the dissolution of metformin hydrochloride tablets should be pH independent. However, 850 mg metformin hydrochloride tablets dissolved more slowly in pH 1.2 and 4.5 dissolution media than in pH 6.8 medium. It is hypothesized that the additional protonation of metformin at the acidic pH results in higher solvation and a larger hydrodynamic radius, leading to slower diffusion and dissolution. This hypothesis was supported by the observation that cationic metformin and anionic sodium lauryl sulfate (SLS), 0.1% (w/v), formed an insoluble salt (1:2 molar ratio) at pH 1.2 and 4.5, but not at pH 6.8. SLS at 0.01% (w/v) in all three media enhanced metformin dissolution. The slower metformin dissolution at pH 1.2 and 4.5 media with SLS can be attributed to the formation of metformin–lauryl sulfate (Met–LS) (1:2 and 1:1) ion pairs, which are more hydrophobic than Met–LS (1:1) ion pairs at pH 6.8. Slower metformin diffusivity in pH 4.5 with 0.05% (w/v) SLS was observed by diffusion-ordered spectroscopy nuclear magnetic resonance. Improved metformin wetting by SLS outweighed the lower diffusivity of metformin-LS ion pairs because similar enhancement in dissolution was noted with 0.5% (w/v) nonionic polysorbate 80.     

Mechanism for the Reduced Dissolution of Ritonavir Tablets by Sodium Lauryl Sulfate

Sodium lauryl sulfate (SLS) is an anionic surfactant widely used in pharmaceutical research as a dissolution enhancer for poorly soluble drugs. When SLS was used in ritonavir (RTV) tablet formulation to improve wetting, dissolution of RTV was surprisingly deteriorated in acidic media. To understand this unexpected phenomenon, a systematic investigation, including solubility determination, intrinsic dissolution rate measurement, dissolution in an artificial stomach and duodenum apparatus, and solid-state characterization, revealed the formation of a poorly soluble salt, [RTV²⁺][LS^?]₂, in an acidic environment. Solubilization of the poorly soluble RTV salt was observed when the concentration of SLS exceeded the critical micelle concentration. Thus, precipitation of [RTV²⁺][LS^?]₂ at a low pH and in presence of a low SLS concentration can lead to deteriorated bioavailability. This unintended negative effect on dissolution should be carefully considered when using SLS in a tablet formulation of a basic drug that can be ionized in gastric fluid.     

Crosslinking studies in gelatin capsules treated with formaldehyde and in capsules exposed to elevated temperature and humidity

Incomplete in vitro capsule shell dissolution and subsequent drug release problems have recently received attention. A modified USP dissolution method was used to follow capsule shell dissolution, and a 2,4,6-trinitrobenzenesulfonic acid (TNBS) assay was used to follow loss of epsilon-amino groups to study this shell dissolution problem postulated to be due to gelatin crosslinking. The dissolution problems were simulated using hard gelatin capsule (HGC) shells previously treated with formaldehyde to crosslink the gelatin. These methods were also used to study the effect of uncrosslinked HGC stored under stressed conditions (37 degrees C and 81% RH) with or without the presence of soft gelatin capsule shells (SGC). A 120 ppm formaldehyde treatment reduced gelatin shell dissolution to 8% within 45 min in water at 37 degrees C. A 200 ppm treatment reduced gelatin epsilon-amino groups to 83% of the original uncrosslinked value. The results also support earlier reports of non-amino group crosslinking by formaldehyde in gelatin. Under stressed conditions, HGC stored alone showed little change over 21 weeks. However, by 12 to 14 weeks, the HGC exposed to SGC showed a 23% decrease in shell dissolution and an 8% decrease in the number of epsilon-amino groups. These effects on the stressed HGC are ascribed to a volatile agent from SGC shells, most likely formaldehyde, that crosslinked nearby HGC shells. This report also includes a summary of the literature on agents that reduce gelatin and capsule shell dissolution and the possible mechanisms of this not-so-simple problem.     

Enhancing the Dissolution Stability of Hard Gelatin Capsules Using Activated Carbon as a Packaging Component

Hard gelatin capsule (HGC) shells are widely used to encapsulate drugs for oral delivery but are vulnerable to gelatin cross-linking, which can lead to slower and more variable in vitro dissolution rates. Adding proteolytic enzymes to the dissolution medium can attenuate these problems, but this complicates dissolution testing and is only permitted by some regulatory authorities. Here, we expand the scope of our previous work to demonstrate that canisters containing activated carbon (AC) or polymeric films embedded with AC particles can be used as packaging components to attenuate gelatin cross-linking and improve the dissolution stability of hard gelatin-encapsulated products under accelerated International Council for Harmonisation conditions. We packaged acetaminophen and diphenhydramine HCl HGCs with or without AC canisters in induction-sealed high-density polyethylene bottles and with or without AC films in stoppered glass vials and stored these samples at 50°C/75% relative humidity through 3 months and at 40°C/75% relative humidity for 6 months. Samples packaged with AC canisters or AC films dissolved more rapidly than samples packaged without AC when differences were observed. These results demonstrate that different sources and formats of AC can enhance the dissolution stability of HGCs packaged in bottles and other potential packaging systems such as blister cards.     

具明胶交联现象的氟伐他汀钠胶囊溶出度方法研究

目的 针对氟伐他汀钠胶囊交联现象建立溶出度试验方法,为修订现行氟伐他汀钠胶囊溶出度标准提供依据。方法 通过比较氟伐他汀钠胶囊国内外现行标准中溶出度方法,比对国内2家公司样品在4种pH条件下的溶出曲线相似度,考察样品在水和木瓜蛋白酶溶液（酶活力≥ 550 U·mL^-1）这2种溶出介质中的平均溶出度,确定溶出度检查方法：桨法,50 r·min^-1,溶出介质为500 mL水,30 min取样,HPLC测定,限度为标示量的80%;若出现不符合规定情况,以含木瓜蛋白酶溶液（酶活力≥ 550 U·mL^-1）为溶出介质,照上述方法重新试验,应符合规定。结果 本品未发生交联样品批次在水和木瓜蛋白酶溶液中的溶出结果一致,发生交联样品批次在加酶溶出介质中平均溶出量提高5%~7%。结论 该方法重现性好、准确、可靠,能客观反映本品的溶出情况,为统一和修订本品现行标准中溶出度项目提供了依据。     

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.     

选用优质明胶改善软胶囊的崩解

目的：解决软胶囊崩解迟缓、崩解不合格的问题。方法：从更换明胶、添加加速溶出辅料、抗氧剂三方面改进囊皮，应用胶片溶解速率法筛选囊皮处方，并进行软胶囊留样考察。结果：加入L-半胱氨酸、柠檬酸，选用优质明胶均有明显的增溶效果，选用优质明胶可解决软胶囊崩解迟缓、崩解不合格的问题。结论：不同厂家生产的明胶质量存在较大差异，选用优质明胶是改善软胶囊崩解迟缓、崩解不合格问题的关键所在。     

麻黄软胶囊的溶出稳定性及影响因素考察

目的：考察中药麻黄软胶囊的溶出稳定性及影响因素,探讨中药软胶囊溶出迟缓机制。方法：采用加速试验,评价麻黄软胶囊的溶出稳定性;以平衡溶胀量和ε-氨基酸残基含量为指标,评价明胶囊壳的交联程度;应用红外光谱和醛类专属反应,鉴定麻黄提取物中醛类成分,并测定其含量。结果：在加速试验条件下（40℃,75％相对湿度）,放置30天后,明胶囊壳的平衡溶胀量和ε-氨基酸残基含量均显著下降（P〈0．01）,其交联度显著增加（P〈0．01）;放置60天后,麻黄软胶囊溶出度显著下降（P〈0．01）。环境因素（高温／高湿）、溶媒介质（聚乙二醇）和药物成分（麻黄提取物）均可导致明胶交联度显著提高（P〈0．01）,其中麻黄提取物的作用明显大于另两种影响因素。麻黄提取物中醛质量分数达约1．6％。结论：麻黄软胶囊溶出迟缓与囊壳明胶发生交联反应有关,而麻黄提取物中醛类成分是促进软胶囊发生交联反应、导致其溶出迟缓的主要原因。     

Stabilization of hard gelatin capsule shells filled with polyethylene glycol matrices

The purpose of this study was to evaluate the effects of various stabilizers on the dissolution stability of liquid-filled capsule dosage forms containing a potent drug dissolved in polyethylene glycols. A systematic dissolution slowdown was observed in gelatin capsule formulations without a stabilizer and was exaggerated under stress storage conditions. This slowdown is attributed to cross-linking of the gelatin shells. Addition of butylated hydroxyanisole (BHA) delayed the onset of gelatin cross-linking, and a combination of BHA with water added to this formulation effectively prevented product dissolution slowdown. For similar formulations filled into hypromellose capsule shells, no dissolution slowdown was observed, even in the absence of stabilizers.     

阿魏酸哌嗪片的溶出曲线考察

目的：建立阿魏酸哌嗪片溶出度曲线测定方法,比较4家生产企业阿魏酸哌嗪片在4种不同溶出介质中的溶出行为差异,为药品质量控制与仿制药一致性评价提供参考。方法：以pH 1.2盐酸溶液、醋酸盐缓冲液（pH 4.0）、磷酸盐缓冲液（pH 6.8）和水为溶出介质,分别考察4家企业12批阿魏酸哌嗪片的溶出曲线,采用f2相似因子法评价溶出曲线的相似性。结果：所有批次样品在pH 1.2盐酸溶液中溶出量均低于15%,3家企业9批次样品在pH 6.8磷酸盐缓冲液和水中的溶出行为相似（f2>50）,pH 4.0醋酸盐缓冲液对阿魏酸哌嗪片有较好区分力。结论：建立的测定方法专属性强、灵敏度高、准确可靠,可用于阿魏酸哌嗪片溶出曲线测定,为其质量控制提供参考。     

In Vitro Dissolution Profile of Water-Insoluble Drug Dosage Forms in the Presence of Surfactants

The determination of the in vitro release profile of water-insoluble drug products requires dissolution media different from those used for water-soluble drug products. Since the relevance of drug dissolution in organic solvents is questionable, we investigated the use of surfactants to determine the dissolution profiles of water-insoluble drug products. In most cases, the drug dissolution rate and extent increased as the surfactant concentration in the aqueous dissolution medium increased. Suitable dissolution profiles were obtained in the presence of sodium lauryl sulfate (SLS) for water-insoluble drug products, such as griseofulvin, carbamazepine, clofibrate, medroxyprogesterone, and cortisone acetate. These findings recommend the use of surfactants for determining the aqueous dissolution of water-insoluble drug products rather than adding organic solvents to the dissolution medium.     

Dissolution of ionizable water-insoluble drugs: the combined effect of pH and surfactant

This study reports the results of the combined effect of pH and surfactant on the dissolution of piroxicam (PX), an ionizable water-insoluble drug in physiological pH. The intrinsic dissolution rate (J(total)) of PX was measured in the pH range from 4.0 to 7.8 with 0%, 0.5%, and 2.0% sodium lauryl sulfate (SLS) using the rotating disk apparatus. Solubility (c(total)) was also measured in the same pH and SLS concentration ranges. A simple additive model including an ionization (PX <--> H(+) + PX(-)) and two micellar solubilization equilibria (PX + micelle <--> [PX](micelle), PX(-) + micelle <--> [PX(-)](micelle)) were considered in the convective diffusion reaction model. J(total) and c(total) of PX increased with increasing pH and SLS concentration in an approximately additive manner. Nonlinear regression analysis showed that observed experimental data were well described with the proposed model (r(2) = 0.86, P < 0.001 for J(total) and r(2) = 0.98, P < 0.001 for c(total)). The pK(a) value of 5.63 +/- 0.02 estimated from c(total) agreed well with the reported value. The micellar solubilization equilibrium coefficient for the unionized drug was estimated to be 348 +/- 77 L/mol, while the value for the ionized drug was nearly equal to zero. The diffusion coefficients of the species PX, PX(-), and [PX](micelle) were estimated from the experimental results as (0. 93 +/- 0.35) x 10(-5), (1.4 +/- 0.30) x 10(-5), and (0.59 +/- 0.21) x 10(-5) cm(2)/s, respectively. The total flux enhancement is less than the total solubility enhancement due to the smaller diffusion coefficients of the micellar species. This model may be useful in predicting the dissolution of an ionizable water insoluble drug as a function of pH and surfactant and for establishing in vitro-in vivo correlations, IVIVC, for maintaining bioequivalence of drug products.     

In situ lyophilisation of nifedipine directly in hard gelatine capsules

Hydrophobic drugs present a challenge due to: (i) adhesion and agglomeration; hence the choice of the suitable processing technique to have the drugs into orally administered dosage forms is critical. (ii) Poor dissolution and poor aqueous solubility; hence poor bioavailability. A novel method which is in situ lyophilisation directly in hard gelatin capsule shells was used in this research to enhance the dissolution of nifedipine (a model hydrophobic drug) in the presence of co-povidone, Pluronic^®F-127 and inulin as enhancement excipients (to the best of our knowledge those excipients have not been previously used with nifedipine in lyophilised forms).

Solutions of nifedipine and excipients in a range of concentrations (0.5, 1, 5 and 10%w/v) were prepared using a co-solvent system of tert- butyl alcohol/water mixture. These solutions were filled directly into bodies of size 000 hard gelatin capsule shells and freeze dried. Pure drug and all formulations were characterised by solubility, wetting studies and in vitro dissolution. Also, conformational integrity and thermal characteristics of nifedipine formulations were investigated using FT-IR spectroscopy and differential scanning calorimetry (DSC), respectively. The in situ lyophilisation of nifedipine with excipients, looks a promising method not only to improve the hydrophobic drug dissolution but also to be cost effective.     

In Vitro and in Vivo Pharmacoscintigraphic Evaluation of Ibuprofen Hypromellose and Gelatin Capsules

PURPOSE: To evaluate the in vitro and in vivo characteristics of hypromellose (HPMC) capsules prepared using a gellan gum and potassium gelling system compared to conventional hard gelatin capsules. METHODS: The in vitro dissolution of ibuprofen gelatin and HPMC capsules was determined using the USP and TRIS buffers at pH 7.2. The effect of pH and composition of the media was determined using a model drug that is soluble throughout the pH range 1.2 to 7.2. In an 11 subject four-way crossover study, the gastrointestinal performance of ibuprofen gelatin and HPMC capsule formulations was evaluated using scintigraphy and pharmacokinetics following fasted and fed dosing. RESULTS: Acid conditions and the presence of K+ cations hinder HPMC capsule opening, whereas in water, dissolution is identical to that of gelatin. These effects are related to the nature of the gel network that is formed in the presence of cations. No significant difference in esophageal transit was observed. Although the in vivo opening times of HPMC capsules were longer than for their gelatin counterparts, no significant difference in the regulatory important pharmacokinetic metrics of C(max) and AUC was found between ibuprofen, gelatin and HPMC capsules. CONCLUSIONS: The in vitro performance of HPMC capsules differ from gelatin, which will require modification to dissolution testing methodology for certain drugs. However, for the class II BCS drug ibuprofen, the two capsule types were not statistically different when comparing AUC and C(max) values, which suggests that the in vitro differences have reduced in vivo relevance.     

阿莫西林胶囊溶出度测定方法研究

目的考察紫外-可见分光光度(UV-Vis)法与高效液相色谱(HPLC)法测定阿莫西林胶囊溶出度的差异。方法 UV-Vis法测定波长为272 nm;HPLC法色谱柱为Inertsil ODS C18柱(150 mm×4.6 mm,5μm),流动相为0.05 mol/L磷酸二氢钾溶液(用2 mol/L氢氧化钾溶液调节pH至5.0)-乙腈(97.5∶2.5,V/V),检测波长为254 nm,进样量为20μL,流速为1.0 m L/min。分别以水、pH 1.2的盐酸氯化钠溶液、pH 4.0的醋酸盐缓冲液、pH 6.8的磷酸盐缓冲液为溶出介质,采用篮法(转速为100 r/min)测定原研产品(参比制剂)的体外溶出量。结果测定参比制剂在以上4种溶出介质中120 min时的溶出度,UV-Vis法分别为109.53%,115.64%,110.02%,114.72%,HPLC法分别为102.54%,77.11%,101.09%,102.24%。结论 HPLC法简单、准确,可用于阿莫西林胶囊溶出度的定量测定,且消除了空胶囊壳的干扰,更能真实地反映产品在溶出介质中的溶出度,可用于阿莫西林胶囊的一致性评价。     

盐酸曲美他嗪片溶出度测定方法的建立

目的:建立测定盐酸曲美他嗪片溶出度的方法。方法:溶出度测定采用桨法,分别以900mL水、pH1.0盐酸溶液和pH6.8磷酸盐缓冲液为溶出介质,转速为50、75、100r·min-1进行溶出条件的筛选。含量测定采用紫外分光光度法,检测波长为232nm。考察样品在30min时的体外溶出情况。结果:确立了以900mL水为溶出介质、桨法转速为50r·min-1的溶出方法;在30min内,样品溶出达到80%以上。结论:所建方法简便、准确、结果可靠,可用于盐酸曲美他嗪片溶出度测定。     

雷贝拉唑钠肠溶片的溶出度研究及方法学验证

目的:针对雷贝拉唑钠肠溶片在偏中性介质中不稳定及存在辅料干扰的情况,建立适宜的溶出度测定方法,考察雷贝拉唑钠肠溶片参比制剂及不同厂家仿制药的溶出度,并对该测定方法进行方法学验证.方法:利用紫外分光光度计,采用等吸收点-双波长吸收差值法测定参比制剂及国内A、B两个厂家仿制药在pH 1.2、pH 6.0、pH 6.8、水4...