Ralph F. Shangraw

Failure of Prescription Prenatal Vitamin Products to Meet USP Standards for Folic Acid Dissolution

OBJECTIVE To determine whether prescription prenatal vitamins meet United States Pharmacopeial Convention (USP) standards for folic acid dissolution. METHODS Dissolution was measured using USP Apparatus II and test conditions specified in the 23rd revision of the United States Pharmacopeia (USP 23). Folic acid was assayed by a chromatographic method modified from that specified in the official monographs, for oil- and water-soluble vitamins with minerals tablets, in USP 23. RESULTS Only three out of nine multivitamin products met USP specifications for folic acid release. Most missed by a wide margin; folic acid dissolution from two products was less than 25%. CONCLUSIONS Because a wide variety of brand-name and generic prescription prenatal multivitamin products were tested, these results are likely to be representative of the multivitamin products on the market. Given the significance of folic acid to public health, the authors believe that this subject should be studied further and that prompt action should be taken to ensure that folic-acid-containing products are of the highest quality possible.

Variable Efficacy of Calcium Carbonate Tablets

Orally administered calcium carbonate tablets are commonly prescribed as a calcium supplement and for their phosphate-binding effects in renal failure patients. Two cases are reported in which a commercially available brand of calcium carbonate tablets appeared to be ineffective. Formal investigation of the bioavailability of this product revealed it to have impaired disintegration and dissolution and a lack of clinical efficacy. Recommendations that will enable physicians to avoid prescribing and pharmacists to avoid dispensing ineffective calcium carbonate tablets are proposed.

The Role of Intra- and Extragranular Microcrystalline Cellulose in Tablet Dissolution

The objective of this study was to examine the influence of intra- and extragranular microcrystalline cellulose (MCC) on drug dissolution from tablets made by high-shear granulation. Granulations were made in a Littleford Model W-10-B (10-liter) mixer and dried in a fluid bed dryer (Niro Inc.). A Plackett-Burman screening design and 2(3) factorial design were employed to study how drug type, MCC (intra- or extra-), filler type (lactose or dicalcium phosphate), disintegrant type (sodium starch glycolate or croscarmellose sodium) and level, proportion of magnesium stearate, and impeller speed affect tablet hardness, disintegration time, and dissolution. Two model drugs were chosen based on their solubility: metoprolol tartrate (solubility > 1000 mg/ml) and hydrochlorothiazide (solubility = 1.05 mg/ml). Tablets were compressed to the same target weight (dose) and similar tablet hardness. In some cases, dissolution testing was also carried out on the loose granules. The intra-extragranular distribution of MCC was found critical to the compactibility and initial dissolution rates from these tablets. Intragranular MCC reduced drug dissolution, the effect being most marked in the case of the slightly soluble hydrochlorothiazide. For formulations containing intragranular MCC, the granulating fluid level on tablet dissolution was also important, since an increase in fluid level resulted in slower drug dissolution from both the loose granules and the tablets compressed from them. Conversely, extragranular MCC tended to increase both dissolution rates and compactibility. It may be concluded that the appropriate distribution of MCC between and within granules may optimize both dissolution and compactibility without changing overall tablet composition.

Characterization of β-cyclodextrin for direct compression tableting: II. The role of moisture in the compactibility of β-cyclodextrin

The role of moisture in the compactibility of β-cyclodextrin has been examined. A physically modified β-cyclodextrin (BCD-DC) was compared to a commercial β-cyclodextrin product (Kleptose®). The moisture sorption-desorption isotherms of both β-cyclodextrin samples showed considerable hysteresis. This can be attributed to the fact that water is associated to β-cyclodextrin in the form of a crystal hydrate. Both β-cyclodextrin samples lost their compactibility on removal of water, thus demonstrating that moisture is essential for the compactibility of β-cyclodextrin. A moisture content of about 14% appears to be optimum for maximum compactibility of samples studied.

Characterization of β-cyclodextrin for direct compression tableting

Abstract A physically modified β-cyclodextrin (BCD-DC) sample was characterized for direct compression tableting. The compactibility of BCD-DC was compared to a commercial β-cyclodextrin product (Kleptose ® ) and other commonly used direct compression fillers. Heckel analysis and mercury porosimetry were used to elucidate the primary deformation mechanism of both β-cyclodextrin (BCD) samples. BCD-DC showed superior compactibility compared to Kleptose ® and excellent dilution potential. Compactibility and dilution potential of BCD-DC were comparable to microcrystalline cellulose. Lubricant sensitivity of BCD-DC was similar to that of microcrystallline cellulose. Tablet strength was found to increase with decrease in particle size. Heckel analysis and mercury porosimetry revealed that BCD-DC and Kleptose ® deform primarily by plastic flow but failed to distinguish between the two samples. Scanning electron photomicrographs and surface area data show that BCD-DC has more irregular and laminated particles than Kleptose ® . These differences in the external particle characteristics rather than internal crystal structure are primarily responsible for the greater compactibility of BCD-DC.

Characterization of the tableting properties of β-cyclodextrin and the effects of processing variables on inclusion complex formation, compactibility and dissolution

AbstractThe tableting properties of a number of commercially available β-cyclodextrins were characterized. Fluidity was insufficient for routine direct compression. Compactibility varied by source but was excellent. Lubrication requirements were minimal. An inclusion complex of β-cyclodextrin/Progesterone was formed and the tableting properties of the complex were compared to those of a physical mixture in both directly compressed and wet granulated products. Inclusion complexes spontaneously formed during wet granulation processing. Substantial differences in tableting properties were found as processing variables were changed. β-cyclodextrin exhibits considerable promise as a standard filler binder in tableting.

Intrinsic Dissolution Rates of Tablet Filler-Binders and Their Influence on the Dissolution of Drugs from Tablet Formulations

Intrinsic dissolution rates were determined for different grades of commonly used calcium salt fillers and lactose. Typical tablet formulations of low-dose drugs were studied to determine the influence of this property on drug dissolution.

Evaluation of Soy Polysaccharide as a Disintegrating Agent Part I: Direct Compression

AbstractSoy polysaccharide, a group of high molecular weight polysaccharides obtained from soy beans, was evaluated as a disintegrant in tablets made by direct compression using lactose and dicalcium phosphate dihydrate as fillers. A cross-linked sodium carboxy-methyl cellulose and corn starch were used as control disintegrants. Parameters studied were compressibility, friability and disintegration times. Dissolution studies were conducted on tablets containing hydrochlorothiazide as a model drug of low water solubility. Soy polysacchardie performs well as a disintegrating agent in direct compression formulations with results paralleling those of cross-linked CMC at the 2% level and superior to corn starch at the 8% level. Dissolution rates of the drug from tablets were rapid, particularly at the 5% level and were not adversely affected by aging at room temperatures.

Evaluation of Soy Polysaccharide as a Disintegrating: Agent Part II: Wet Granulation

Soy polysaccharide was evaluated as a disintegrating agent in tablets made by wet granulation utilizing both lactose and dicalcium phosphate dihydrate as fillers, gelatin as a granulating agent and hydrochlorothiazide as a model drug. It was found to be more effective than starch but less effective than cross-linked carboxymethylcellulose (Ac-Di-SolR) at equivalent concentrations. Soy polysaccharide appears to reduce the friability of tablets as concentration increases. Tablets containing either Soy polysaccharide or cross-linked carboxymethylcellulose showed no changes in dissolution profiles after storage under ambient conditions for six months.

Nitroglycerin analysis: spurious low concentrations with the automated U.S.P. content uniformity assay in the presence of dextrose

Recent interest in nitroglycerin (glycerol trinitrate, GTN) has been stimulated by its re-emergence as a potential drug of first choice in treating post-myocardial infarction patients (Dean & Baun 1975; Flaherty et al 1975). Since neither 0.9% NaCl or sterile water were suitable vehicles for i.v. administration, 5 % dextrose was adopted; but when GTN solutions for i.v. use were prepared for hospital use, an initial significant decrease in concentration was found in the dextrose solutions. This report describes the reason for this apparent decrease. All reagents were analytical grade unless indicated otherwise. Acetonitrile was from Burdick and Jackson (glass distilled, Muskegon, MI). Standard solutions of GTN were made from GTN spirit standardized against potassium nitrate using the U.S.P. phenoldisulphonic procedure (U.S.P., 1975a), GTN solutions for assay were prepared by diluting GTN spirit to 7.5, 15 or 22.5 pg ml-I with 0, 1, 3, or 5 ” / , dextrose in water. The U.S.P. content uniformity procedure (U.S.P., 1975b) for the analysis of GTN was used as described by Bell (1964) with the following modifications. The concentration of N-( I-naphthy1)ethylenediamine dihydrochloride (NEDD) was reduced to 0.25 from 1 mgml I to stabilize the baseline, the number of samples per hour was reduced to 20 to allow better separation between samples and the ratio of sample to wash was 1 : 4. Three standard samples were run at the beginning of each series and one standard was run after every 10 samples. The sensitivity of the assay was 5 pg ml-I. The method revealed an initial significant decrease in GTN concentration which was repeated subsequently. To determine if this was related to dextrose concentration, GTN solutions were prepared as above and assayed immediately. Solutions in 5 % dextrose yielded apparent G T N concentrations about 15% less than those in water at each G T N concentration. Increasing the dextrose concentration led to decreasing GTN concentration, indicating that the problem was definitely related to the dextrose concentration. Increasing the concentration of the assay reagents and the temperature proved futile while dextrose assayed alone produced no apparent interference with the assay. At this point it was unclear whether the concentration difference was the result of rapid GTN