Sunil S. Jambhekar

Cyclodextrins in pharmaceutical formulations I: structure and physicochemical properties, formation of complexes, and types of complex.

Cyclodextrins are cyclic oligosaccharides that have been recognized as pharmaceutical adjuvants for the past 20 years. The molecular structure of these glucose derivatives, which approximates a truncated cone, bucket, or torus, generates a hydrophilic exterior surface and a nonpolar interior cavity. Cyclodextrins can interact with appropriately sized drug molecules to yield an inclusion complex. These noncovalent inclusion complexes offer a variety of advantages over the noncomplexed form of a drug. Cyclodextrins are primarily used to enhance the aqueous solubility, physical chemical stability, and bioavailability of drugs. Their other applications include preventing drug-drug interactions, converting liquid drugs into microcrystalline powders, minimizing gastrointestinal and ocular irritation, and reducing or eliminating unpleasant taste and smell. Here, we discuss the physical chemical properties of various cyclodextrins, including the effects of substitutions on these properties. Additionally, we report on the regulatory status of their use, commercial products containing cyclodextrins, toxicological considerations, and the forces involved in complex formation. We also highlight the types of complex formed and discuss the methods used to determine the types of complex present.

Investigation of the Applicability of Ion Exchange Resins as a Sustained Release Drug Delivery System Forpropranolol Hydrochloride

AbstractThe purpose of this study was to investigate the application of six strongly acidic cation exchange resins as a sustained release drug delivery system. Propranolol hydrochloride was chosen as the model drug to study the in vitro adsorption and desorption characteristics of the resins because of its chemical structure and pharmacokinetie properties which make it a good candidate for a sustained release formulation. The exchange rate constants and diffusion coefficients for the adsorption and desorption experiments were determined for each resin using the equations derived by Boyd, Adamson and Myers. Only one cation exchange resin showed potential as a sustained release drug delivery system for propranolol hydrochloride.

Factors Affecting the Release of Propranolol Hydrochloride from Beads Coated with Aqueous Polymeric Dispersions

AbstractThe main objective of this study was to investigate the release kinetics and mechanism involved in the transport of an ionizable drug through polymeric films applied to drug-loaded beads. The influence of factors such as drug loading and membrane thickness on release kinetics were also investigated. Beads containing propranolol hydrochloride were coated with either of two commercially available aqueous polymeric dispersions, Aquacoat® or Sure lease®, using the Wurster-Process. Analysis of the drug release data suggest that the drug release followed zero-order release kinetics. The plots of drug release constants versus the reciprocal of membrane thickness were found to be linear for both polymeric dispersions. Increasing the osmotic pressure of the dissolution medium was found to decrease the mass of drug released at any given time for both Aquacoat® and Surelease® coated beads. Hence, drug release from these spherical membrane reservoir systems appeared to be diffusion controlled accompanied by o...

Solid-state β-cyclodextrin complexes containing indomethacin, ammonia and water. I. Formation studies

In a previous report five unique complexes were prepared and characterized containing β-cyclodextrin, indomethacin, ammonia and water. In this study the solubility, dissolution behavior, complex-binding constant, crystallinity and enthalpy were assessed. The results show indomethacin solubility was improved by complex formation with β-cyclodextrin. There was little difference among the various complex solubilities. Indomethacin dissolution was improved by complex formation with the exception of one complex. Indomethacin dissolution profiles were found to differ and were unrelated to either the complexed indomethacin content or binding constant. Indomethacin dissolution profiles were found to be related to the complex crystallinity and enthalpy. The complex-binding constants were found to support a theory reported previously that β-cyclodextrin ring cavity solvation was the predominant factor responsible for complex formation.

Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency

Cyclodextrins are cyclic oligosaccharides that have been recognized as pharmaceutical adjuvants for the past 20 years. The molecular structure of these glucose derivatives, which approximates a truncated cone, bucket, or torus, generates a hydrophilic exterior surface and a nonpolar interior cavity. Cyclodextrins can interact with appropriately sized drug molecules to yield an inclusion complex. These noncovalent inclusion complexes offer a variety of advantages over noncomplexed forms of a drug. Cyclodextrins are carbohydrates that are primarily used to enhance the aqueous solubility, physical chemical stability, and bioavailability of drugs. Their other applications include preventing drug-drug interactions, converting liquid drugs into microcrystalline powders, minimizing gastrointestinal and ocular irritation, and reducing or eliminating unpleasant taste and smell. Here, we focus on the solubilization of drugs by complexation, and discuss the determination and significance of binding constants for cyclodextrin complexes, and the determination of complexation efficiency and factors that influence it. We also make some general observations on cyclodextrin complexation and the use of cyclodextrins in solid, as well as parenteral, dosage forms.

Drug dissolution: significance of physicochemical properties and physiological conditions

Oral bioavailability of a drug is determined by a number of properties, including drug dissolution rate, solubility, intestinal permeability and pre-systemic metabolism. Frequently, the rate limiting step in drug absorption from the gastrointestinal tract is drug release and drug dissolution from the dosage form. Therapeutic agents with aqueous solubilities less than 100μg/ml often present dissolution limitations to absorption. Physicochemical, formulation-related and physiological factors can all influence drug dissolution. In this review, the authors will discuss the important physicochemical properties of a drug and physiological conditions in the gastrointestinal tract that play an important part in drug dissolution and absorption processes and, consequently, the bioavailability of a drug.

A fluorimetric liquid chromatographic method for the determination of propranolol in human serum/plasma

A simple, rapid, and sensitive fluorimetric-high-performance liquid chromatographic method for the determination of propranolol in human serum/plasma has been developed, without the need for solvent extraction. The procedure required 200 microliters of serum/plasma, and the addition of 1 ml of acetonitrile for protein precipitation followed by vortexing and centrifugation at 10 000 g. The clear supernatant was evaporated to dryness under a stream of nitrogen at 50-60 degrees C, the residue was reconstituted in 100 microliters of methanol, and a 90 microliters portion was injected onto the high-performance liquid chromatograph for propranolol quantitation. Chromatography was accomplished using a Hypersil cyano column, a mobile phase of acetonitrile-aqueous acetic acid (1%) containing 0.2% triethylamine (35:65, v/v) (pH 3.6), a flow rate of 1.5 ml min-1, a fluorescence detector set at an excitation wavelength of 230 nm and an emission wavelength of 340 nm, and using pronethalol as the internal standard. Retention times for pronethalol and propranolol were 7.5 min and 9.5 min, respectively. Standard curves were linear in the range 5-200 ng ml-1. Relative standard deviations for both inter-day and intra-day precision analysis were less than 7% for serum. No interference was observed from endogenous serum/plasma components. Specificity was shown for some, but not all, commonly coadministered drugs tested. The advantages of this method include good precision, low sample volume, good reproducibility and recovery, and high sensitivity.

Bioavailability and In-vitro/in-vivo Correlation for Propranolol Hydrochloride Extended-release Bead Products Prepared Using Aqueous Polymeric Dispersions

The influence of formulation and extrinsic factors has been investigated for the in‐vitro release of propranolol hydrochloride from controlled‐release beads prepared using aqueous polymeric dispersions, Aquacoat and Surelease. A single‐dose three‐way crossover bioavailability study of two extended‐release experimental formulations (80 mg), Inderal LA (80 mg) and an Inderal immediate‐release dosage form (2 × 40 mg) was also conducted and a comparative analysis of pharmacokinetic parameters and the in‐vitro release profiles was performed to assess in‐vitro/in‐vivo correlation.

Influence of Formulation and Other Factors on the Release of Chlorpheniramine Mateate from Polymer Coated Beads

AbstractControlled release beads containing chlorpheniramine maleate, coated with Eudragit RL and RS, were prepared using the Wurster process. The effect of membrane thickness, polymer ratio of the coating material, agitation speed and pH of the dissolution medium on drug release were investigated using the USP dissolution basket method. The in vitro release of drug was described adequately by a previously published equation. The release rate constant (K) was dependent on the membrane thickness, the polymer ratio and pH of the dissolution medium. On the other hand, agitation speed used in this study did not have any influence on the release of the drug.

Dried Molasses as a Direct Compression Matrix for Oral Controlled Release Drug Delivery II: Release Mechanism and Characteristics of Theophylline from a Molasses-Hpmc Matrix

AbstractInvestigation was conducted to evaluate dried molasses as a direct compression matrix for oral controlled release drug delivery system based on its tendency to form a gel-like layer around an inner dry core tablet when it comes in contact with fluid. Dried molasses matrix was modified by incorporation of hydroxypropylmethylcellulose (HPMC) at four concentration levels (12.5, 15.0, 20.0 and 28.57%) to obtain a gel layer of suitable characteristics, and compressed directly on an instrumented rotary tablet press. Theophylline was used as a model drug. Drug release study was performed using USP dissolution apparatus 2, rotated at 20 rpm, in distilled water, simulated gastric fluid pH 1.2, and simulated intestinal fluid pH 7.5. Theopylline was determined by a High Pressure Liquid Chromatographic method, utilizing beta-hydroxyethyl theophylline (BHET) as an internal standard. Results showed an inverse relationship between the rate of release and the level of HPMC, with release period ranging from 3 to 3...