Enhancing the Dissolution Stability of Hard Gelatin Capsules Using Activated Carbon as a Packaging Component.

Hard gelatin capsule (HGC) shells are widely used to encapsulate drugs for oral delivery but are vulnerable to gelatin cross-linking, which can lead to slower and more variable in vitro dissolution rates. Adding proteolytic enzymes to the dissolution medium can attenuate these problems, but this complicates dissolution testing and is only permitted by some regulatory authorities. Here, we expand the scope of our previous work to demonstrate that canisters containing activated carbon (AC) or polymeric films embedded with AC particles can be used as packaging components to attenuate gelatin cross-linking and improve the dissolution stability of hard gelatin-encapsulated products under accelerated International Council for Harmonisation conditions. We packaged acetaminophen and diphenhydramine HCl HGCs with or without AC canisters in induction-sealed high-density polyethylene bottles and with or without AC films in stoppered glass vials and stored these samples at 50°C/75% relative humidity through 3 months and at 40°C/75% relative humidity for 6 months. Samples packaged with AC canisters or AC films dissolved more rapidly than samples packaged without AC when differences were observed. These results demonstrate that different sources and formats of AC can enhance the dissolution stability of HGCs packaged in bottles and other potential packaging systems such as blister cards.

Use of Activated Carbon in Packaging to Attenuate Formaldehyde-Induced and Formic Acid-Induced Degradation and Reduce Gelatin Cross-Linking in Solid Dosage Forms.

Formaldehyde and formic acid are reactive impurities found in commonly used excipients and can be responsible for limiting drug product shelf-life. Described here is the use of activated carbon in drug product packaging to attenuate formaldehyde-induced and formic acid-induced drug degradation in tablets and cross-linking in hard gelatin capsules. Several pharmaceutical products with known or potential vulnerabilities to formaldehyde-induced or formic acid-induced degradation or gelatin cross-linking were subjected to accelerated stability challenges in the presence and absence of activated carbon. The effects of time and storage conditions were determined. For all of the products studied, activated carbon attenuated drug degradation or gelatin cross-linking. This novel use of activated carbon in pharmaceutical packaging may be useful for enhancing the chemical stability of drug products or the dissolution stability of gelatin-containing dosage forms and may allow for the 1) extension of a drug product's shelf-life when the limiting attribute is a degradation product induced by a reactive impurity, 2) marketing of a drug product in hotter and more humid climatic zones than currently supported without the use of activated carbon, and 3) enhanced dissolution stability of products that are vulnerable to gelatin cross-linking.

Dissolution Similarity Requirements: How Similar or Dissimilar Are the Global Regulatory Expectations?

The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globally divergent regulatory requirements to meet local dissolution similarity requirements. In effect, experiments customized to meet the current international regulatory expectations for dissolution and drug release unnecessarily increase manufacturing costs, hinder science and risk-based approaches, increase collective regulatory burden, reduce continuous improvement and innovation, and potentially delay patient access to urgently needed medication. Comparative assessment of regulatory differences in applying dissolution to demonstrate product similarity is crucial to reduce non-scientifically justified experiments and foster collaborative harmonization among global regulatory health authorities and the pharmaceutical industry.

Rapid identification and absence of drug tests for AG-013736 in 1mg Axitinib tablets by ion mobility spectrometry and DART™ mass spectrometry.

Axitinib (AG-013736) is a potent investigational drug that has antitumor activity in patients with metastatic renal cell carcinoma and other types of cancers. In this study, ion mobility spectrometry and "direct analysis in real time" (DART™) mass spectrometry were used to rapidly identify AG-013736 in drug substance samples and 1mg Axitinib tablets. The plasmagrams of the sample solutions exhibited a major peak with a reduced ion mobility that was within ±0.0002cm(2)V(-1)s(-1) of that for AG-013736 in an external reference standard solution. The DART ionization source was coupled with both a time-of-flight mass spectrometer and a lower-resolution ion trap mass spectrometer. Samples were analyzed by this technique in as little as 5s with minimal to no sample preparation required. The isotopic masses of the protonated dimer ions of AG-013736 were used to identify AG-013736 in the active tablet. Both techniques were also used to develop low-level limit tests for rapidly verifying the presence or absence of AG-013736 in blinded clinical supplies of active and matching placebo tablets of Axitinib.

Osmotic capsules: A universal oral, controlled-release drug delivery dosage form.

An osmotic, oral, controlled-release capsule is described. This capsule provides drug delivery at fixed delivery rates (T(80%)=6 or 14h) independent of drug properties (e.g., solubility) or drug loading, thereby allowing rapid development of investigational or commercial drugs, especially for proof-of-concept type clinical studies. The capsule body and cap are prepared with cellulose acetate and polyethylene glycol in acetone and water using high density polyethylene molds as templates and a conventional tablet pan coater. After the shells are removed from the molds manually, a laser hole is drilled in the end of the capsule body. The drug is introduced as a shaped tablet admixed with polyethylene oxide. A "push" tablet consisting of high molecular weight polyethylene oxide, microcrystalline cellulose, and sodium chloride is also inserted into the capsule body. The capsule halves lock together due to ridges, alleviating the need for a banding operation.

Statistical assessment of dissolution and drug release profile similarity using a model-dependent approach.

A general multivariate procedure for assessing the similarity of dissolution and drug release profiles was developed. A mathematical model is fit to the data, and Hotelling's T(2) test is used to calculate the joint confidence region around the vector of differences between least-squares estimates of the parameters in the model. The method of Lagrange multipliers is used to determine if this confidence region is enclosed within a predetermined similarity region, and profile similarity is claimed if this is the case. The first-order, Gompertz, logistic, second-order, and Weibull models were fit to the in vitro extended-release profile of pseudoephedrine HCl from an asymmetric membrane (AM) film-coated osmotic tablet. The first-order model was selected because of its simplicity and because it was the best-fitting model according to a modified form of Akaike's Information Criterion. A nonlinear response surface model was also developed so that the formulator could calculate how much of the AM film coat should be applied in order to obtain the desired drug release profile. The usefulness of this model-dependent procedure was further demonstrated during an analytical method transfer exercise, where it was used to compare the drug release profiles obtained by two independent laboratories; additional research is required, however, before the appropriate acceptance criteria for demonstrating profile similarity can be recommended.

Development and validation of a dissolution test for a once-a-day combination tablet of immediate-release cetirizine dihydrochloride and extended-release pseudoephedrine hydrochloride.

A dissolution test for a once daily combination tablet containing 10 mg of cetirizine dihydrochloride (cetirizine HCl) for immediate release and 240 mg of pseudoephedrine hydrochloride (pseudoephedrine HCl) for extended release was developed and validated according to current ICH and FDA guidelines. The cetirizine HCl is contained within an outer layer of the tablet while a semipermeable membrane of cellulose acetate and polyethylene glycol controls the rate at which pseudoephedrine HCl is released from the tablet core. The dissolution method, which uses USP apparatus 2 with paddles rotating at 50 rpm, 1000 ml of deaerated water as the dissolution medium, and reversed-phased HPLC for quantitation, was demonstrated to be robust, discriminating, and transferable. These test conditions were selected after it was demonstrated that the cetirizine HCl portion of the tablet rapidly dissolved in aqueous media over the physiologically relevant pH range of 1.1-7.5, and that the extended-release profile of pseudoephedrine HCl was independent of dissolution conditions (i.e., apparatus, pH, and agitation).