Bashar A. Alkhalidi

A Validated RP HPLC-PAD Method for the Determination of Hederacoside C in Ivy-Thyme Cough Syrup

A simple reversed phase high-performance liquid chromatographic (RP-HPLC) method coupled with a photodiode array detector (PAD) has been developed and validated for the analysis of hederacoside C, the marker of ivy plant, in Ivy-Thyme cough syrup. Separation of hederacoside C was achieved using a Phenomenex-Gemini C18 column isothermally at 40°C. A mobile phase system constituted of solvent A (water: acetonitrile: orthophosphoric acid (85%), 860 : 140 : 2 v/v) and solvent B (acetonitrile: orthophosphoric acid (85%), 998 : 2 v/v) was used, at gradient conditions, at a flow rate of 1.5 mL/min. Analysis was performed using UV-detection (205 nm). The method was linear over the range (0.03–0.15) mg/mL of hederacoside C (r = 0.9992). Repeatability and intermediate precision were acceptable (RSD <2%). Limits of detection (LOD) and quantitation (LOQ) were 0.011 and 0.032 mg/mL, respectively. Percentage recovery was found to lie between 99.69% and 100.90% (RSD <2%). The method was also proved to be specific (peak-purity coefficient = 0.996).

Modulation of buspirone HCl release from hypromellose matrices using chitosan succinate: implications for pH-independent release.

Chitosan succinate (CS) was synthesized through the acylation of chitosan with succinic anhydride. The interaction of CS with buspirone HCl (BUSP) was evaluated using dialysis experiments and shown to result in complex with a stability constant of 2.26 mM and a capacity of 0.0362 micromol BUSP/mg CS. The extent of complexation upon dry and wet mixing of CS and BUSP was determined quantitatively using differential scanning calorimetry. The extent of the interaction was highest in wet mixtures and was found to be dependent on the pH of the granulation liquid. CS was incorporated in BUSP-containing hypromellose (HPMC) tablets using dry mixing and wet granulation with BUSP. Tablet dissolution was tested in 0.1N HCl and phosphate buffer, pH 6.8. According to f(2) and mean dissolution time results, the similarity of profiles increased as CS content increased with the highest f(2) value observed when CS was wet granulated with BUSP. Dissolution was also tested in deionized water and 5% NaCl; where increased ionic strength resulted in faster dissolution suggesting an ion exchange involvement in drug release. CS was proved effective in modulating BUSP release from HPMC matrices for pH-independent release through ionic complex formation.

Effects of Thermal Curing Conditions on Drug Release from Polyvinyl Acetate–Polyvinyl Pyrrolidone Matrices

This study aimed to investigate the effects of dry and humid heat curing on the physical and drug release properties of polyvinyl acetate–polyvinyl pyrrolidone matrices. Both conditions resulted in increased tablet hardness; tablets stored under humid conditions showed high plasticity and deformed during hardness testing. Release from the matrices was dependent on the fillers type and level. Release profiles showed significant changes, as a result of exposure to thermal stress, none of the fillers used stabilized matrices against these changes. Density of neat polymeric compacts increased upon exposure to heat; the effect of humid heat was more evident than dry heat. Thermograms of samples cured under dry heat did not show changes, while those of samples stored under high humidity showed significant enlargement of the dehydration endotherm masking the glass transition of polyvinyl acetate. The change of the physical and release properties of matrices could be explained by the hygroscopic nature of polyvinyl pyrrolidone causing water uptake; absorbed water then acts as a plasticizer of polyvinyl acetate promoting plastic flow, deformation, and coalescence of particles, and altering the matrices internal structure. Results suggest that humid heat is more effective as a curing environment than dry heat for polyvinyl acetate–polyvinyl pyrrolidone matrices.

Assessment of the bioequivalence of two formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions: A single-dose, randomized, open-label, two-period, two-way crossover study in healthy Jordanian male volunteers

BACKGROUND Clarithromycin extended-release tablets are indicated for the treatment of adults with acute maxillary sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae; acute bacterial exacerbation of chronic bronchitis due to H influenzae, Haemophilus parainfluenzae, M catarrhalis, or S pneumoniae; or community acquired pneumonia due to H influenzae, H parainfluenzae, M catarrhalis, S pneumoniae, Chlamydia pneumoniae, or Mycoplasma pneumoniae. OBJECTIVE This study was conducted to assess the bioequivalence of test and reference formulations of clarithromycin extended-release 500-mg tablets under fasting and fed conditions. METHODS This was a single-dose, randomized, open-label, 2-period, 2-way crossover study with a 1-week washout period between doses. Separate bioequivalence studies (fasting and fed) were performed in 2 groups of healthy male Jordanian volunteers. Eighteen blood samples were obtained from each volunteer over 38 hours after drug administration. Clarithromycin concentrations were determined in plasma using a validated high-performance liquid chromatography method with electrochemical detection. Pharmacokinetic parameters of clarithromycin (C(max), T(max), AUC(0-t), AUC(0-infinity), lambda(z) [first-order elimination rate constant], and t((1/2))) were calculated and analyzed statistically. Tolerability was assessed based on changes in vital signs and laboratory tests, and by questioning subjects about adverse events. RESULTS Thirty-eight volunteers each participated in the fasting and fed studies. The mean ages of participants in the fasting and fed studies were 26.7 and 27.6 years, respectively; their mean weight was 71.2 and 70.9 kg and mean height was 171.3 and 179.0 cm. Under fasting conditions, the arithmetic mean (SD) C(max) was 569.4 (189.3) ng/mL for the test formulation and 641.2 (202.0) ng/mL for the reference formulation, with a geometric mean ratio of 0.88. The arithmetic mean AUC(0-t) was 8602.9 (4105.1) and 8245.3 (4122.4) ng . h/mL in the respective formulations, with a geometric mean ratio of 1.06. The arithmetic mean T(max) was 8.0 (5.6) and 6.1 (3.8) hours. In the fed study, the C(max) and AUC of both formulations were significantly increased relative to the fasting study (P < 0.05). The arithmetic mean C(max) of the 2 formulations was 1183.0 (637.5) and 1199.6 (496.3) ng/mL, with a geometric mean ratio of 0.93. The arithmetic mean AUC(0-t) was 12,981.2 (7849.0) and 11,822.9 (5790.2) ng . h/mL, with a geometric mean ratio of 1.06. The arithmetic mean T(max) was 5.7 (2.8) and 6.7 (2.5) hours. The 90% CI for the ratio (test:reference) of log-transformed C(max) and AUC values was within the acceptance range of 0.80 to 1.25. The 2 formulations were both well tolerated, and no adverse events were reported during the study. CONCLUSIONS In these fasting and fed studies in healthy male Jordanian volunteers, the 2 formulations of clarithromycin extended-release 500-mg tablets were found to be bioequivalent according to the US Food and Drug Administration regulatory definition. Administration with food significantly increased the rate and extent of absorption of both products, with no significant effect on their bioequivalence.

Application of active layering and coating techniques in the development of a multiparticulate, controlled release dosage form of a high-dose, highly soluble drug

Abstract Context: The success of the development of controlled release, multilayered, multiparticulate dosage form of a high-dose, highly-soluble drug is dependent upon proper material and processing choices. Objective: To develop a controlled release dosage form of diltiazem hydrochloride using active layering and coating. Methods: Active layering was achieved by spraying a drug solution onto sugar cores using polyvinyl alcohol – polyethylene glycol as a binder. Layered pellets with highest loading and lowest binder content were coated using aqueous dispersions of polyvinyl acetate (PVAc). The effects of the plasticizer and curing on drug release were evaluated. Results and discussion: The binder level had no effect on the process efficiency. Drug release from PVAc-coated pellets was slowed by increasing PVAc level. Plasticization slowed drug release in comparison to nonplasticized formulations. Curing affected drug release of nonplasticized formulations only. Protection against humidity was essential in stabilizing drug release under stability study conditions. Conclusion: Materials and process used were suitable to face the challenge posed by the high dose of the water-soluble drug on the success of the formulation. The effects of the plasticizer, curing and ability of packaging to protect against elevated humidity on the performance of the studied system should be considered in development.

Comparative Dissolution of Diltiazem Immediate and Extended Release Products Using Conventional USP and Innovative Dissolution Paddles~!2009-11-24~!2010-01-12~!2010-04-28~!

Drug dissolution studies are commonly conducted using compendial methods employing USP Paddle and Basket apparatuses. In many cases, dissolution studies can be of limited benefit especially for product-dependent dissolu- tion procedures like in extended release (ER) formulations. The high variability in dissolution testing, that is not product- related, emphasizes the need for developing new methods for dissolution testing that can address the artifacts found with the current USP dissolution methods. A crescent shaped spindle was suggested as a solution to overcome drawbacks associated with conventional dissolution methods. Diltiazem immediate- and extended-release tablets and capsules were used to evaluate the crescent-shaped spindle and compare it to the USP paddle system. Appropriate dissolution rates were obtained using crescent-shaped spindle at 25 rpm compared to higher rotation speeds of 75/100 rpm with the USP Paddle. Similarity factor (F2) and dissolution efficiency (DE) parameters were used to evaluate dissolution profiles. Statistical analysis using student t-test and P-value was used to compare the results under various test conditions. For the immediate release (IR) products, only one product out of four had similar dissolution profile in the USP paddle and Crescent shaped spindles. Two products out of five ER products were found similar based on the F2 value. In general, Crescent shaped spindle provided better evaluation for the dissolution of IR and ER products without any evidence of harsh stirring environment or crushing.

Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations

The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50 rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1 h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed.

Comparative Randomized, Single‐Dose, Two‐Way Crossover Open‐Label Study to Determine the Bioequivalence of Two Formulations of Dalfampridine Tablets

Dalfampridine is a medication that is approved by the US Food and Drug Administration to improve walking impairments in patients with multiple sclerosis (MS). The branded dalfampridine is enormously expensive; hence, the availability of generic dalfampridine will provide better access to the medication, especially for uninsured patients with MS. Bioequivalence studies are demanded by the regulatory authorities to allow the marketing of new generics of dalfampridine. The aim of this study was to assess the bioavailability of the generic (test) and branded (reference) formulations of 10 mg dalfampridine of extended‐release tablets after oral administration to healthy adults under fed conditions. The current report methodology was based on a comparative, randomized, single‐dose, 2‐way crossover open‐label study design. Twenty‐seven subjects were given a single dose of the test dalfampridine tablet and completed the clinical study. The pharmacokinetic parameters Cmax and AUC0→t, Kel, AUC0→∞, tmax, and t1/2el were estimated to prove bioequivalence. The confidence intervals for the log‐transformed test/reference ratios for dalfampridine 100.96% (97.09%–104.97%) and 99.77% (95.81%–103.87%) for Cmax and AUC0→∞, respectively, were within the allowed limit specified by the regulatory authorities (80%–125%). Hence, clinically, the test tablet can be prescribed as an alternative to the reference for the indication of improving walking impairments in patients with MS.

An Investigation into Formulation and Processing Strategies to Drive Gastroretention of Gabapentin Tablets

PurposeThe aim of the present work was to develop gastroretentive drug delivery system of gabapentin from different matrices prepared by hot melt or conventional wet granulation, which may enhance drug bioavailability. The influence of core type, granulation process, and coating level on the drug release rates was investigated.MethodsTablet cores were prepared from hydrophilic system of hypermellose, carboxy melthyl celloulse, and Avicel or hydrophobic system of ethyl cellulose, alginic acid, and stearic acid. The tablets were coated by Eudragit RL with triethyl citrate and compressed directly. These tablets were evaluated according to their in vitro dissolution profiles and release mechanisms.ResultsHydrophobic matrices allowed the control of drug release. Hot melt granulation was an effective tool over wet granulation or coating for slowing release rates from hydrophobic tablets. Both hydrophobic polymer ratio and coating level influenced the drug release mechanism. The drug release of samples with minor proportion of ethyl cellulose and stearic acid or low Eudragit RL level was driven by anomalous transport and the increase of their proportions contributed to the erosion of the matrix.ConclusionsHydrophobic core tablet prepared from hot melt granulation and coated by Eudragit RL has shown to be a promising formulation intended to gastroretentive gabapentin delivery system.