Compendial Tests Research Articles

Quantification of 5 -HMF and dextrose in commercial aqueous dextrose solutions

5-Hydroxymethylfurfural (5-HMF) is the major thermal decomposition product formed in aqueous dextrose solutions during sterilization and upon storage. Current compendial tests employ a spectrophotometric assay for 5-HMF and a separate assay based on optical rotation for dextrose. Efforts herein focused on identification of approaches to simultaneously quantify both 5-HMF and dextrose in aqueous solutions. Initial studies employed anion exchange chromatography with pulsed amperometric detection (PAD). These studies showed that the low anion exchange column loading capacity and concentration mismatch of dextrose and 5-HMF in typical commercial solutions makes simultaneous quantitation impractical at a single sample concentration. However, mixed modes of detection for each analyte using refractive index (RI) detection for dextrose and UV detection for 5-HMF proved viable for simultaneous quantitation. The performance of both approaches was evaluated and extremely high sensitivity for 5-HMF demonstrated (30–50 ppb). The formation of 5-HMF upon the forced thermal decomposition of dextrose was monitored and compared with results from the USP spectrophotometric assay.

Evaluation of floating and sticking extended release delivery systems: an unconventional dissolution test

The extent to which hydrophilic matrix tablets with a propensity to stick to the dissolution apparatus and/or float are susceptible to variations in hydrodynamic conditions during dissolution testing was investigated. Furthermore the usefulness of simple alternatives to the current compendial tests is examined. Swellable hydrocolloid (guar) matrix tablets containing verapamil HCl were evaluated using USP dissolution apparatus I and II. Two additional configurations where an additional single ring and mesh device or a double mesh device was located below the paddle in the dissolution vessel were also evaluated. Tablets were placed on top of the single mesh device or in the compartment formed by the two mesh surfaces of the double mesh device. In all cases near linear (n≥0.82) release profiles were observed. When using apparatus I it was observed that the highly swellable tablets were fully constricted by the basket within 5–7 h. This prevented further independent movement and unimpeded swelling and coincided with a departure from linear release and increased variability (S.D.≤9.5%). Under standard apparatus II conditions two out of three tablets adhered to the bottom of the dissolution vessel for the duration of the experiment. Consequently their release profiles differed markedly from those obtained under apparatus I conditions (similarity factor, f2=30.5) with the release rate being approximately half of that obtained under apparatus I conditions. Adhesion to the dissolution vessel was also observed when paddle speed was doubled to 100 rpm, thus again resulting in large variability (S.D.≤34%). Whilst the averaged single and double mesh configuration profiles were similar to the apparatus I profile (f2=57.36 and 61.38, respectively), large variability (S.D.≤11%) occurred with the single mesh configuration due to floating and random adhesion of tablets to the paddle or sampling tubes. Almost superimposable profiles were obtained for the individual tablets (S.D.<3%) when the tablets were located in the compartment formed by the double mesh device. Use of a double mesh device may therefore provide an alternative to current compendial dissolution methods when the reliable determination of the true release kinetics of floating and sticking delivery systems is desired.

Optimized and Validated HPLC Methods for Compendial Quality Assessment. III. Testing of Optical Purity Applying α1-Acid-Glycoprotein Stationary Phase

Since distomer impurity in the compendia enantiomer may indicate the lack of careful purification or an ability of racemization, the control of enantiomeric purity has growing significance. Although α1 - acid - glycoprotein (AGP) stationary phase was applied for the separation of a number of drug enantiomers, it was hardly used for testing of enantiomer purity. In this work the suitability of AGP column for compendial control of enantiomeric purity is illustrated by methods optimized through the selection of optimal quality (phosphate, acetate), pH (4.0; 5.5; 6.0; 7.0) and concentration (0.01, 0.03, 0.06 M) of the buffer-eluent and the best organic modifier (isopropanol, acetonitrile, dioxane). The chromatographic behavior of four basic, three acidic, and one neutral compound is interpreted. In the case of propranolol and ibuprofen, 5% impurity may be detected while, in the case of norgestrel, 2.5% of the impurity may be detected. Recommendations for compendial testing are presented.

MEDICAL AEROSOLS: TECHNIQUES FOR PARTICLE SIZE EVALUATION

ABSTRACT Methods for the in-vitro measurement of the particle size distribution of aerosols from medical aerosol delivery systems, including pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers, are reviewed with emphasis on their applicability both for compendial testing and for simulation of patient use. The importance of real-time measurement techniques, particularly for routine quality control testing, is also discussed, despite the current lack of a means to obtain absolute measurements of drug mass with these systems.

Optimized and validated HPLC Methods for Compendial Quality Assessment I. Methylxanthine Derivatives

The HPLC method suggested here is suitable for the detection and quantitative determination of 0.1–1 % caffeine, theobromine and theophylline impurities in each of these methylxanthine derivatives. The system optimization includes organic modifier content, ionic strength, eluent flow rate and concludes to the use of a simple C18/methanol-water 1:4 (I = 0.1) chromatographic system. The limit of impurity detection was found to be 15 ng (theobromine, theophylline) and 30 ng (caffeine). The range of quantitation extends from 31.25 to 250 ng. The accuracy (percentage of recovery) and precision (repeatability) of the method are tabulated. The method, considering validation requirements of USP XXIII, demonstrates the suitability of HPLC for selective compendial purity tests.

Bioequivalence assessment of generic drugs: an American point of view.

Consistent quality and performance characteristics for the innovator (brand name) drug products and their generic (multisource) equivalents are explicit objectives of the drug approval process in the US. Statutory and regulatory requirements supporting these objectives are based on the bioavailability and bioequivalence Regulations (1), the amendments to the Food, Drug and Cosmetic Act (2), and the implementing regulations to the amendments. These objectives are based on the concept that an innovator drug exists with reproducible quality and performance characteristics that are maintained throughout the marketing life. Following termination of the patent or the exclusivity period for an innovator drug product, its generic pharmaceutical equivalents may be marketed. These generic drug products are expected to demonstrate comparable quality and performance characteristics to those of the innovator product throughout the marketing period. In addition, both innovator and generic drug products may undergo several post-approval changes in formulation and manufacturing processes, change of manufacturing site, and increase in batch size, etc., that may warrant demonstration of sustained quality and performance characteristics. Several drug application and compendial tests and specifications exist to assure the overall objective of stability in the quality and the performance characteristics of the innovator and

Diaspirin crosslinked hemoglobin (DCLHb): characterization of the process and the product manufactured under GMP requirements for clinical studies.

Initiation of Clinical Trials in 1992 necessitated product manufacture under FDA Good Manufacturing Practice (GMP) requirements. To this end, all product components used were characterized to meet established requirements and processes and analytical methods were validated to confirm and document their utility and reproductibility. Manufacture of multiple 50+ liter lots of 10%g DCLHb under GMP requirements resulted in a pure and homogeneous product which reproducibly met a rigorous and complete set of product specifications. Final release testing of five consecutive GMP lots showed hemoglobin concentrations of 10.2 +/- 0.2g%, pH of 7.33 +/- 0.02 (37 degrees C), methemoglobin concentrations of 3.2 +/- 0.6%, degree of crosslinking of 99.8 +/- 0.1% and a P50 of 32.4 +/- 1.0 mmHg (37 degrees C). The mean overall yield for production of these five lots was 55 +/- 2%. Products were all endotoxin free as indicated by rabbit, cytokine and LAL testing (< 0.06 EU/mL); a critical characteristic for a molecule which may bind endotoxin. All lots were sterile as indicated by compendial testing.

Exact Power Function of Compendial Test Requirements for Content Uniformity

AbstractThe exact distributions associated with the current compendial test requirements are generated by resorting to the well known Computer Intensive Algorithm method to establish the exact percentage point (limit) for RSD, corresponding to each selected cut-off probability level (confidence level) for each of the four possible experimental outcomes based on the USP-NF test requirements. A table is constructed to present the two-dimensional power function. The similarities between these tabular values and the current compendial RSD limits for 10 and 30 dosage units are extremely remarkable.Minor differences exist, however. It is suggested that both the theoretical as well as the numerical approaches should be carried out to arrive at a comprehensive solution.

Near-infrared spectroscopy as an alternative to assess compliance of ampicillin trihydrate with compendial specifications

The suitability of near-infrared spectroscopy (NIRs) as an alternative to several compendial test methods such as identification, water content and assay, in the release procedure of drug substances is demonstrated with ampicillin trihydrate as an example. It is also shown that in cases in which a manufacturing process is well under control, a 'standard activity' can be assigned to a batch when its conformity with 'standard quality' is proven by means of its NIR spectrum. For that purpose a new quality parameter--the Conformity Index (CI)--is introduced.

The use of near infrared spectroscopy in the quality control laboratory of the pharmaceutical industry

The suitability of NIR spectroscopy as an alternative to several compendial test methods is discussed. Using ampicillin trihydrate as an example it is demonstrated that eight quality criteria are controlled by recording the NIR spectrum of a batch sample and calculating its Conformity Index.

A Simplified TLC System for Qualitative and Semi-Quantitative Analysis Of Pharmaceuticals

Abstract There is a need at pharmacies, ports of entry, etc. for inexpensive rapid screening methods which could be used to determine if the right drug is present in the right amounts. These areas usually do not have ready access to full laboratory services for compendial testing. Such a method has been developed using thin-layer chromatography (TLC) making it possible to analyze drugs in areas without laboratory services. Solutions of the drug sample are spotted along with reference materials and the intensities visually compared. Since most drugs are colorless in white light, it is necessary to treat the developed chromatogram with some visualizing agent. Several different categories of pharmaceuticals have been made visible in white light by dipping the plate into a solution of iodine-KI. The stained spots make it possible to determine the drug content qualitatively and quantitatively within the range of specifications. The iodine staining method has been found to be a general method.

Selection of Optimum Dissolution Test Methods in Dosage Form Design

AbstractThe rate limiting factors involved in release of a drug from a tablet are generally accepted to be the disintegration of the tablet followed by the subsequent dissolution of the drug from the dispersed granules.The development of new potencies of an existing tabletted product by weight multiplication was found to result in non-conformance to established specifications for the product not formulation related.In addition to a study of the rate limiting factors mentioned above compendial dissolution tests were also compared. Apparatus II was shown to produce more rapid and consistent results than Apparatus I in this investigation and this test is recommended as the one of choice where large volume compacts are involved.

Impaired HLA capping capacity of peripheral blood lymphocytes in Duchenne muscular dystrophy.

The cap capacity in nine Duchenne muscular dystrophy (DMD) patients and in 23 healthy male subjects (14 adults and nine neonates) has been investigated by inducing capping of HLA molecules. The evaluation of capping percentages ranged in healthy controls from 44 to 61 with a mean value of 53.39 +/- 4.89, while DMD patients displayed cap capacity of percentages varying from 15 to 38 with a mean value of 31.5 +/- 7.42. Statistical significance of the differences between the two groups, assessed by the Mann-Whitney U test, was p less than 0.00003. A correlation was found in DMD patients between cap capacity and age (tau = +0.657, p = 0.012). The results confirm previous reports of Ig capping impairment noted in B cells of the whole lymphocyte population, supporting the hypothesis of a systemic cellular defect in DMD patients. The data obtained suggest that HLA capping could overcome some of the technical difficulties of Ig capping and could be used as a diagnostic aid in antenatal detection of DMD.

A Simple Method for Differentiating Sources of Pregelatinized Starch Nf

AbstractA simple test procedure to differentiate between sources of pregelatinized starch NF has been developed. The procedure is based on the swelling characteristics of the materials. Three pregelatinized starch NF products were distinguished by observing their sedimentation volumes. Microscopic differences in the particle morphology of each starch product were also observed. The study indicates that sedimentation testing can be used as an addition to the current compendial identity tests for pregelatinized starch NF.

Technical Problems of the USP/NF Dissolution Test

The USP/NF dissolution test (Method I or rotating-basket method) was applied to different commercial tablet formulations of sulfisoxazole, sulfamethoxazole, and tolbutamide. It was found that the hydrochloric acid solution required for testing the sulfa drug tablets corroded the basket so that it could not be used after 40 hr. of exposure to the acid. Because the dissolution time of a sulfamethoxazole formulation in phosphate buffer (pH 7.2) was close to that obtained using compendial conditions, it is suggested that the official dissolution medium could be replaced, with advantage, by the phosphate buffer. The dissolution times of nine different sulfisoxazole formulations tested in a less acidic medium were not comparable in rank order and magnitude to those obtained with the compendial test. Dissolution times of eight different tolbutamide formulations in phosphate buffer (pH 7.6) were similar in rank order and magnitude to those obtained with the compendial test. It is suggested that this buffer replace the tromethamine [tris-(hydroxymethyl)aminomethane] buffer, currently official, which has a large temperature coefficient of pH.