A comparative study of the dissolution characteristics of capsule and tablet dosage forms of melt granulations of paracetamol--diluent effects

The dissolution characteristics of melt granulations of paracetamol in capsule and tablet dosage form were compared to determine whether the dissolution characteristics of the granules can be actualized by formulating them as rapidly disintegrating tablets. The term melt granulation refers here to the wax-matrix granules that were formed by triturating the drug powder (paracetamol) with a melted carnauba wax. The matrix granules were admixed with diluents (lactose, alpha-cellulose or microcrystalline cellulose) also in granular form to prevent size separation during encapsulation or tableting. The granules were filled into hard gelatin capsules (mean content weight, 500 +/- 6.2 mg) or tableted (mean weight 500 +/- 5.1 mg, and tensile strength 1.36 +/- 0.2 to 1.7 +/- 0.3 MN/m2). The capsules and tablets were subjected to disintegration and in vitro dissolution tests. The dissolution data were analyzed on the basis of zero, first order rate kinetics and Higuchi square root of time relationship. The results showed that the dissolution profiles were generally consistent with a first order rate kinetics (r = 0.95). The first order dissolution rate constants of capsules and tablets of the matrix granules only (without diluents) were 0.31 +/- 0.02 min(-1) and 0.20 +/- 0.03 min(-1), respectively, indicating faster dissolution from the capsules. Therefore, the dissolution characteristics of the matrix particles were not intact after tableting. Addition of diluents to the capsule formulations had no effect on dissolution rates, whereas in the tablets, dissolution rates increased. For instance, inclusion of a diluent up to 50% w/w in the tablets increased the dissolution rate constants to 0.34 +/- 0.04 min(-1) (lactose), 0.42 +/- 0.02 min(-1) (alpha-cellulose), and 0.46 +/- 0.03 min(-1) (microcrystalline cellulose). Thus, alpha-cellulose and microcrystalline cellulose produced greater enhancer effect on the tablet dissolution rates compared to lactose. Both the capsules and the tablets disintegrated rapidly within 2 to 3 minutes. The dissolution enhancer effect of the diluents in the tablets only, relates to the aqueous swelling of the disintegrated particles.     

Properties of lipophilic matrix tablets containing phenylpropanolamine hydrochloride prepared by hot-melt extrusion.

The objective of the present study was to investigate the influence of formulation factors on the physical properties of hot-melt extruded granules and compressed tablets containing wax as a thermal binder/retarding agent, and to compare the properties of granules and tablets with those prepared by a high-shear melt granulation (MG) method. Powder blends containing phenylpropanolamine hydrochloride, Precirol and various excipients were extruded in a single-screw extruder at open-end discharge conditions. The extrudates were then passed through a 14-mesh screen to form granules. The extrusion conditions and the optimum amount of wax to function as the thermal binder were dependent on the properties of the filler excipients. At the same wax level, drug release from tablets decreased in the order of using microcrystalline cellulose (MCC), lactose and Emcompress as the filler excipient. The observed differences in the dissolution properties of the tablets were due to the differences in the solubility, swellability and density of the filler excipients. Replacing Precirol with Sterotex K, a higher melting point wax, resulted in slightly increased dissolution rates, when the extrusion was performed at the same temperature conditions. Hot-melt extruded granules were observed to be less spherical than high-shear melt granules and showed lower values of bulk/tap densities. However, tablets containing MCC or lactose granules prepared by hot-melt extrusion (HME) exhibited higher hardness values. Slower drug release rates were found for tablets containing MCC by HME compared with MG. Analysis of the hot-melt extruded granules showed better drug content uniformity among granules of different size ranges compared with high-shear melt granules, resulting in a more reproducible drug release from the corresponding tablets.     

Theophylline serum levels unmodified by postprandial administration of a sustained-release preparation (Teonova)

The authors studied serum theophylline levels after administration of new single-dose capsules: Teonova. Special attention was paid to possible fluctuations of serum theophylline after administration of the drug following a standardized meal. For this purpose a test was carried out on eight male patients with intrinsic asthma. The patients were given a dose able to produce a serum concentration of theophylline of between 10 mcg and 20 mcg at the tenth hour after the administration. This dose was found to be 400 mg (2 tablets of 200 mg) for one patient and 600 mg (2 tablets of 300 mg) for the remaining seven. The capsules of Teonova were administered to each patient for two subsequent days at 07h00. On the first day the patients had their capsules after fasting, and on the second day after a standardized meal. The test proved that Teonova assured a satisfactory serum theophylline level throughout the 24 hours in all patients; food in no way affected the absorption kinetics of the drug. Such features make Teonova suitable for long-term theophylline therapy.     

Evaluation of xanthan and highly substituted galactomannan from M. scabrella as a sustained release matrix

A highly substituted galactomannan (G) from Mimosa scabrella Bentham (Man:Gal 1.1:1), isolated from the seeds of a Brazilian leguminous tree and xanthan (X), an exopolysaccharide secreted by Xanthomonas campestris (Keltrol), were evaluated as a hydrophilic matrix system (XG) for controlled release (CR) of diclofenac sodium (DS) in tablets and capsules. The performance of XG (2:1) matrices containing 50 mg (A) or 100 mg (B) of DS was compared with a commercial CR product of DS. The drug release studies were carried out using a dissolution apparatus (paddle method) with gradual increase of pH values, from pH 1.4, to pH 4.0 (after 1 h) and to pH 6.8 (after 2 h). The results suggested the potential of XG systems as release retarding materials, which released 78.6 and 35.1% of drug after 24 h for capsules (A) and tablets (A), respectively. Drug release decreased with the increase of amount of drug and it is dependent of dosage form. Analysis of release data indicate a rather zero-order drug release with the erosion mechanism playing a dominant role.     

Formulation study and drug release mechanism of a new theophylline sustained-release preparation

Two matrix theophylline tablets with different release mechanisms were compared. Tablet A was a swelling/disintegration-type wax matrix made of hydrophobic wax granules, consisting of stearic acid, hydrogenated oil and glycerol esters of fatty acids, and hydrophilic polymer granules composed primarily of hydroxypropyl methylcellulose (HPMC). We named Tablet A the cluster tablet. Tablet B was a gel matrix made of hydrophobic ethylcellulose granules, consisting of ethylcellulose and hydrogenated oil, and hydrophilic polymer granules consisting of HPMC and hydroxylpropylmethylcellulose acetate succinate (HPMCAS). The formulations were screened in vitro according to their dissolution characteristics. The drug release from each preparation was analyzed using release kinetics theories. In Tablet A, the value of the exponent(n) representing the apparent diffusion mechanism determined from the Korsmeyer-Peppas model equation was about 0.6 and was unlikely to be affected by the rotation speed. In Tablet B, the value of the exponent(n) by the Korsmeyer-Peppas model equation changed with the paddle rotation speed. These results suggested that the drug release mechanism of Tablet B is greatly affected by the extent of physical force in the gastrointestinal tract.     

快速崩解茶碱包衣小丸骨架片的研制

用挤出／滚圆法以茶碱主模型药物研制快速崩解包衣小丸骨架片,以Ｅｕｄｒａｇｉｔ ＮＥ３０Ｄ或ＲＬ／ＲＳ３０Ｄ为包衣材料,用底喷式流化床包衣,再压制成骨架片,对包衣材料的种类、压片辅料的组成和用量,压片力等因素进行了考察优化,得到了符合美国药典释放度要求的包衣小丸骨架片。     

高脂食物对氨茶碱控释片药代动力学的影响

本文采用荧光偏振免疫分析法,对6名健康受试者空腹或食用高脂早餐后立即服单剂量氨茶碱控释片的血药浓度进行测定,并计算其药代动力学参数。结果表明,高脂食物显著降低氮茶碱控释片的吸收速率,T_(max)从空腹状态下的3.53±0.44h上升至6.54±2.08h(p<0.01),AUC_0→∞增加20％,但无显著差异(p>0.05)。两组的C_(max)、Ke、t_(1/2)和CL没有明显改变。提示高脂肪食物能延缓氨茶碱控释片的吸收,不影响其体内代谢过程和吸收量。由于起效时间减慢,可能会影响临床治疗效果。     

Release, absorption and elimination of theophylline from fast and slowly released oral formulations

Each 2 tablets of four tablet formulations with 150 mg theophylline were administered to 6 and 5 volunteers, respectively, as single oral dose. 8 volunteers received 256 mg theophylline as a solution and as a sustained released formulation, as well as 176 mg theophylline as short intravenous bolus infusion. The elimination was independent of the examined formulations, but differences occurred between the experiments with the different groups of volunteers. The invasion parameters (t1/2i) of the four fast released tablet formulations corresponded to the values (t1/2a) of the oral theophylline solution. Furthermore, no difference existed concerning the mean times (Tsys). The mean time (theophylline) for the body model, Tvss, is 9.9 h; the mean time, which is attributed to the absorption process (Tabs) is 0.7 h; the mean in vivo dissolution time (Tdiss-vivo) for the sustained release formulation is 6.3 h. The mean time after oral administration of the theophylline solution (Tbiol) is 10.6 h. General conditions for a comparison between the in vitro and the in vivo release data are reported.     

Preparation and evaluation of press-coated aminophylline tablet using crystalline cellulose and polyethylene glycol in the outer shell for timed-release dosage forms

In an attempt to achieve chronopharmacotherapy for asthma, press-coated tablets (250 mg), which contained aminophylline in the core tablet in the form of low-substituted hydroxypropylcellulose (L-HPC) and coated with crystalline cellulose (PH-102) and polyethylene glycol (PEG) at various molecular weights and mixing ratios in the amounts of PH-102 and PEG as the outer shell (press-coating material), were prepared (chronopharmaceutics). Their applicability as timed-release (delayed-release) tablets with a lag time of disintegration and a subsequent rapid drug release phase was investigated. Various types of press-coated tablets were prepared using a tableting machine, and their aminophylline dissolution profiles were evaluated by the JP paddle method. Tablets with the timed-release characteristics could be prepared, and the lag time of disintegration was prolonged as the molecular weight and the amount of PEG, for example PEG 500,000, in the outer shell were increased. The lag time of disintegration could be controlled by the above-mentioned method, however, the pH of the medium had no effect on disintegration of the tablet and dissolution behavior of theophylline. The press-coated tablet (core tablet:aminophylline 50 mg, L-HPC and PEG 6000; outer shell:PH-102:PEG = 8:2 200 mg) with the timed-release characteristics was administered orally to rabbits for an in vivo test. Theophylline was first detected in plasma more than 2 h after administration; thus, this tablet showed a timed-release characteristics in the gastrointestinal tract. The time (tmax) required to reach the maximum plasma theophylline concentration (Cmax) observed after administration of the press-coated tablet was significantly (p < 0.05) delayed compared with that observed after administration of aminophylline solution in the control experiment. However, there was no difference in Cmax and area under the plasma theophylline concentration-time curve (AUC0-->24) between the press-coated tablet and aminophylline solution. These results suggest that the press-coated aminophylline tablet (with the timed-release characteristic) offers a promising forms of theophylline chronotherapy for asthma.     

Effects of tableting pressure on hydration kinetics of theophylline anhydrate tablets.

The effects of tableting pressure on hydration kinetics of types I and II theophylline anhydrate tablets at 95% relative humidity, 35 degrees C, have been studied by using various kinetic equations. Relations between tablet expansion and hydration were studied. Samples of 2 cm diameter tablets (1 g) were compressed at 5, 10 and 20 MPa. The hydration of types I and II tablets decreased with increased tableting pressure. The time required for 50% hydration of 2 cm diameter tablets, compressed at various pressures suggests that the tablet hydration rate was affected by the tableting pressure. Types I and II tablets expanded 11.37-16.75% in volume during hydration to the monohydrate. The thickness expansion of the tablets exceeded the diameter expansion as the tablet structure was not uniform owing to the orientation of particles during the compression. The final expansion ratio of the tablets increased with increased tableting compression pressure. The Hancock Sharp constant (m) and fitting of the kinetic data to a suitable model suggested that the hydration of theophylline anhydrate tablets followed the two-dimensional phase boundary equation (type I tablets) or the three-dimensional phase boundary equation (type II tablets).     

Drug release from a new family of graft copolymers of methyl methacrylate. I.

Hydrophilic matrices are an interesting option when developing an oral drug release device. In this work we have produced hydrophilic matrices tablets by direct compression. Previously graft copolymers were synthesized as an important component of the tablets: hydroxypropyl starch-methyl methacrylate (HS-MMA), carboxymethyl starch-MMA (CS-MMA) and hydroxypropyl cellulose-MMA (HC-MMA). The polymeric component was mixed with Emcompress®, stearic acid and theophylline. All the products fulfilled the requirements for good flow according to literature. L-formulations show lower values of plasticity than O-formulations. However, L-formulations exhibit higher compactibility values than O-formulations. In general, all the formulations with O-polymers show faster release of the drug at three pHs used. On the other hand, these tablets have the capacity to hydrate quickly forming a gelatinous layer, so it is necessary to achieve controlled drug release from hydrophilic matrices. In relation with the dissolution efficiency over 8 h, formulations with HS-MMAL and NaCMC show very similar results, although the release of theophylline from NaCMC tablets at different pHs was always slightly slower than HS-MMAL tablets.     

用渗滤理论研究乙基纤维素骨架片的最适压片力范围

目的　用渗滤理论研究制备阿司匹林-乙基纤维素骨架片的最适压片力范围。方法　使用不同的压片力(3～30 kN)制备了含阿司匹林40%的阿司匹林-乙基纤维素骨架片,测定了溶出曲线,用Higuchi方程和Ritger-Peppas方程对溶出数据进行拟合。将拟合的Higuchi方程的斜率b值和计算得到的片剂的孔隙率ε,代入渗滤理论推导出的公式中,可计算出表观扩散系数D和片剂溶出性能参数β,分别以D对ε及β对ε回归,可得到临界孔隙率ε_c,由β-ε,D-ε和β-ε₀曲线可推知最适压片力范围。结果　压片力在9～18 kN时,药物释放遵从Higuchi模型方程,片剂以骨架扩散机制释药,且释药速度适中,因此9～18 kN为最适压片力范围。低于9 kN时,片子的初始孔隙率太大,药物溶出过快;高于18 kN时,药物溶出过慢,呈异常扩散机制释放药物。结论　渗滤理论可较清楚地阐明阿司匹林骨架片的释药机制,并可得到制备阿司匹林片的最适压片力范围。     

Exploration of Novel Co-processed Multifunctional Diluent for the Development of Tablet Dosage Form

The aim of this investigation was to develop a novel multifunctional co-processed diluent consisting of microcrystalline cellulose (Avicel PH 102), crospovidone (Polyplasdone XL) and polyethylene glycol 4000. Colloidal silicon dioxide and talc were also incorporated as minor components in the diluent to improve tableting properties. Melt granulation was adopted for preparation of co-processed diluent. Percentage of Avicel PH 102, Polyplasdone XL and polyethylene glycol 4000 were selected as independent variables and disintegration time was chosen as a dependent variable in simplex lattice design. The co-processed diluent was characterised for angle of repose, bulk density, tapped density, Carr''s index, percentage of fines and dilution potential study. Acetaminophen and metformin were used as poorly compressible model drugs for preparation of tablets. The blend of granules of drug and extra-granular co-processed diluent exhibited better flow as compared to the blend of drug granules and physical mixture of diluents blend. The diluent exhibited satisfactory tableting properties. The tablets exhibited fairly rapid drug release. In conclusion, melt granulation is proposed as a method of preparing co-processed diluent. The concept can be used to bypass patents on excipient manufacturing.     

Bioavailability of a new sustained-release theophylline capsule in fasted and non-fasted healthy subjects: single and multiple dosing studies

Eighteen healthy, non-smoking, adult volunteers participated in single and multiple dose three-way crossover studies to evaluate a sustained-release, pellet-filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained-release capsule was investigated by administering 300 mg single doses of Austyn, with a high-fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p greater than 0.05) between the three regimens with respect to AUC0-infinity values (mg h l-1), (mean +/- SD); Elixophyllin fasting = 97.1 +/- 33.7, Austyn with food = 90.9 +/- 31.3, Austyn fasting = 91.2 +/- 33.8. Similarly, multiple dosing with rapid-release Nuelin tablets, Austyn capsules, and sustained-release Theo-Dur tablets demonstrated that there were no significant differences between regimens with respect to AUC0-24h, AUC0-12h, and AUC12-24h values calculated from the steady-state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady-state over the total blood sampling period was significantly less for treatment with the sustained-release capsule. Austyn, compared with the sustained-release tablet, Theo-Dur (Austyn = 36.7 +/- 13.7 per cent, Theo-Dur = 53.1 +/- 14.1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high-fat meal and with no evidence of dose dumping.     

Eudraginated polymer blends: a potential oral controlled drug delivery system for theophylline

Sustained release (SR) dosage forms enable prolonged and continuous deposition of the drug in the gastrointestinal (GI) tract and improve the bioavailability of medications characterized by a narrow absorption window. In this study, a new strategy is proposed for the development of SR dosage forms for theophylline (TPH). Design of the delivery system was based on a sustained release formulation, with a modified coating technique and swelling features aimed to extend the release time of the drug. Different polymers, such as Carbopol 71G (CP), sodium carboxymethylcellulose (SCMC), ethylcellulose (EC) and their combinations were tried. Prepared matrix tablets were coated with a 5 % (m/m) dispersion of Eudragit (EUD) in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for micromeritic properties, drug concentration and in vitro drug release. It was found that the in vitro drug release rate decreased with increasing the amount of polymer. Coating with EUD resulted in a significant lag phase in the first two hours of dissolution in the acidic pH of simulated gastric fluid (SGF) due to decreased water uptake, and hence decreased driving force for drug release. Release became faster in the alkaline pH of simulated intestinal fluid (SIF) owing to increased solubility of both the coating and matrixing agents. The optimized formulation was subjected to in vivo studies in rabbits and the pharmacokinetic parameters of developed formulations were compared with the commercial (Asmanyl(?)) formulation. Asmanyl(?) tablets showed faster absorption (t(max) 4.0 h) compared to the TPH formulation showing a t(max) value of 8.0 h. The C(max) and AUC values of TPH formulation were significantly (p < 0.05) higher than those for Asmanyl(?), revealing relative bioavailability of about 136.93 %. Our study demonstrated the potential usefulness of eudraginated polymers for the oral delivery of the sparingly soluble drug theophylline.     

In vitro and in vivo evaluation of single-unit commercial immediate-and sustained-release capsules compared with multiple-unit polystyrene microparticles dosage forms of indomethacin

The objective of this study is to select a multiple-unit sustained-release formulation and to compare it with both commercial immediate and single unit sustained-release capsules and also to determine whether an in vitro-in vivo correlation exists for single- and multiple- unit formulations. Indomethacin (20-60% w/w)-loaded, multiple-unit polystyrene microparticles were prepared by emulsion-solvent evaporation method from an aqueous system. The in vitro release profiles obtained in phosphate buffer of pH 6.8 for drug-loaded polystyrene microparticles and for commercial sustained-release capsules (Indocap-SR, 75 mg) were compared. As the microparticles with 50% indomethacin load showed a release profile comparable to that of the Indocap-SR release profile, the microparticles with this drug load was considered as optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in human volunteers. In spite of significantly higher C(max), Ka, and Ke, and lower T(max), t1/2a, t1/2e and AUC(0 --> infinity)) values observed with commercial Microcid immediate-release capsules, there was no sign of difference among the listed parameters between optimized microparticles and Indocap-SR capsules. Indeed, the values of retard quotient (Rdelta) calculated from half-value duration analysis did not show any statistical difference, indicating the occurrence of an almost same degree of retardation of drug release from the optimized microparticles and the Indocap-SR capsules. Furthermore, linear relationship obtained between the percentages dissolved and absorbed suggests a means to predict in vivo absorption by measuring in vitro dissolution. The results suggest that the optimized polystyrene microparticles could provide an alternative controlled-release drug delivery system for indomethacin.     

单剂量口服茶碱缓释胶囊的人体生物等效性评价

目的选择12名男性健康志愿者,进行单剂量口服茶碱缓释胶囊的人体生物等效性评价。方法采用反相高效液相色谱法,以紫外273nm为检测波长,测定了单剂量口服200mg国产茶碱缓释胶囊受试药品在健康人体内的茶碱浓度,并与进口茶碱缓释胶囊参比药品进行对照。结果茶碱缓释胶囊的体内动态过程呈一级吸收的一房室开放模型,国产受试药品和进口参比药品的Cmax分别为(5.12±0.74)mg/L和(5.14±0.63)mg/L,tmax分别为(5.4±1.0)h和(5.3±1.1)h,MRT分别为(17.79±1.48)h和(17.61±1.78)h,t1/2分别为(10.55±0.75)h和(10.59±1.10)h,AUC0-36分别为(85.33±10.56)mg*h/L和(86.26±8.80)mg*h/L。结论以体内茶碱AUC0-36数值表征的国产茶碱缓释胶囊的相对生物利用度为(98.9±6.4)%;选择Cmax、AUC0-36和AUC0-∞进行三因素方差分析与双单侧t检验,结果表明国产茶碱缓释胶囊和进口茶碱缓释胶囊两种制剂具有生物等效性。     

Slow release theophylline disposition and effect in elderly patients with chronic obstructive lung disease: influence of dose formulation and institutionalization

We studied the steady-state disposition of slow release theophylline tablets and granules in 12 institutionalized (I) and 12 community-dwelling (C) elderly patients with fixed chronic obstructive lung disease. Design was open label with random order crossover; each formulation was given 5 min before food every 12 h for 7 days. Age (median 70 y, range 55-88), sex, smoking status, and baseline lung function off drug were similar. Though plasma concentration (Cp) was higher with the tablets as was the area under the Cp vs time curve: 134 (74-252) vs 121 (75-197) mg h l-1; p = 0.028. The standard deviation of Cp over one dose interval was lower with the granules. FEV 1.0 was slightly improved over baseline. Dose required to reach target Cp was higher in the institutionalized group (12.6 vs 8.6 mg kg-1 day-1; p = 0.003) as was apparent clearance; I:94 (43-148) ml hr-1 kg-1 vs C:68 (34-163); p = 0.003. Although bioavailability was slightly reduced for the granules, fluctuations of Cp was less, and we failed to find a food effect that was clinically important in geriatric subjects.     

新型茶碱口服结肠靶向给药系统的体内动力学

目的研究以时间为释药开关的结肠靶向给药系统。方法以非pH依赖型聚丙烯酸树脂Eu dragit NE 3 0D为膜材 ,制备茶碱薄膜衣片 ;用HPLC法进行体内血药浓度分析 ;以γ 闪烁照相研究该制剂体内胃肠道的转运情况。结果本制剂与参比制剂主要药代动力学参数分别为 :tlag( 8 67± 1 0 4 )h、( 0 67± 1 1 5 )h ;Cmax( 5 2 5± 1 2 1 )mg/L、( 4 0 9± 1 2 5 )mg/L ;AUC0 2 6 ( 2 7 5 0±7 2 0 )mg·h/L、( 3 9 0 4± 1 0 4 3 )mg·h/L ;体内γ 闪烁照相研究表明 ,体外 6 5h释放的制剂口服8 0h后到达升结肠处开始释药 ,且体内释药与体外释药有一定的相关性。结论本制剂能达到结肠靶向释药的设计要求     

Fatty acid and water-soluble polymer-based controlled release drug delivery system

Sustained release capsule formulations based on three components, drug, water-soluble polymer, and water-insoluble fatty acid, were developed. Theophylline, acetaminophen, and glipizide, representing a wide spectrum of aqueous solubility, were used as model drugs. Povidone and hydroxypropyl cellulose were selected as water-soluble polymers. Stearic acid and lauric acid were selected as water-insoluble fatty acids. Fatty acid, polymer, and drug mixture was filled into size #0 gelatin capsules and heated for 2 h at 50 °C. The drug particles were trapped into molten fatty acid and released at a controlled rate through pores created by the water-soluble polymer when capsules were exposed to an aqueous dissolution medium. Manipulation of the formulation components enabled release rates of glipizide and theophylline capsules to be similar to commercial Glucotrol XL tablets and Theo-24 capsules, respectively. The capsules also exhibited satisfactory dissolution stability after exposure to 30 °C/60% relative humidity (RH) in open Petri dishes and to 40 °C/75% RH in closed high-density polyethylene bottles. A computational fluid dynamic-based model was developed to quantitatively describe the drug transport in the capsule matrix and the drug release process. The simulation results showed a diffusion-controlled release mechanism from these capsules.