Application of QbD principles for the evaluation of empty hard capsules as an input parameter in formulation development and manufacturing.

Understanding the product and process variable on the final product performance is an essential part of the quality-by-design (QbD) principles in pharmaceutical development. The hard capsule is an established pharmaceutical dosage form used worldwide in development and manufacturing. The empty hard capsules are supplied as an excipient that is filled by pharmaceutical manufacturers with a variety of different formulations and products. To understand the potential variations of the empty hard capsules as an input parameter and its potential impact on the finished product quality, a study was performed investigating the critical quality parameters within and in between different batches of empty hard gelatin capsules. The variability of the hard capsules showed high consistency within the specification of the critical quality parameters. This also accounts for the disintegration times, when automatic endpoint detection was used. Based on these data, hard capsules can be considered as a suitable excipient for product development using QbD principles.

Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration.

The encapsulation of liquids and semi-solids provides solutions for convenient delivery through improved oral absorption of poorly water-soluble drugs. In addition, low dose (content uniformity), highly potent (containment), low melting point drugs, those with a critical stability profile and those for which a delayed release is required are candidates for liquid or semi-solid formulations. Both hard and soft capsules can be considered and in each case the capsule wall may comprise gelatin or some other suitable polymer such as hypromellose. The choice of a hard or soft capsule will depend primarily on the components of the formulation which provides the best absorption characteristics as well as on the physical characteristics, such as the viscosity of the formulation and the temperature at which the product needs to be filled. Numerous excipients are available for formulation of lipid-based systems and their compatibilities with hard gelatin capsules have been tested. The availability of new enhanced manufacturing equipment has brought new opportunities for liquid-filled hard capsules. Filling and sealing technologies for hard capsules, provides the formulator with the flexibility of developing formulations in-house from small scale, as required for Phase I studies, up to production.

Enteric coated HPMC capsules designed to achieve intestinal targeting.

The enteric coating of HPMC capsules containing paracetamol was investigated. Two enteric polymers, Eudragit L 30 D-55 and Eudragit FS 30 D were studied, which are designed to achieve enteric properties and colonic release, respectively. The capsules were coated in an Accela Cota 10, and, as shown by optical microscopy, resulted in capsules with a uniform coating. Scanning electron microscopy of the surface of the capsules illustrate that, in contrast to gelatin, HPMC has a rough surface, which provides for good adhesion to the coating. Dissolution studies demonstrated that capsules coated with Eudragit L 30 D-55 were gastro resistant for 2 h at pH 1.2 and capsules coated with Eudragit FS 30 D were resistant for a further 1 h at pH 6.8. The product visualisation technique of gamma scintigraphy was used to establish the in vivo disintegration properties of capsules coated with 8 mg cm(-2) Eudragit L 30 D-55 and 6 mg cm(-2) Eudragit FS 30 D. For HPMC units coated with Eudragit L 30 D-55, complete disintegration occurred predominately in the small bowel in an average time of 2.4 h post dose. For HPMC capsules coated with Eudragit FS 30 D, complete disintegration did not occur until the distal small intestine and proximal colon in an average time of 6.9 h post dose.

Bio-relevant dissolution testing of hard capsules prepared from different shell materials using the dynamic open flow through test apparatus.

Current compendial dissolution and disintegrating testing is unable to mimic physiological conditions affecting gastric drug release from immediate release dosage forms. In order to obtain more realistic data, a novel test setup was developed that we term a 'dynamic open flow through test apparatus'. It is based on the previously described dissolution stress test device and attempts to simulate the intra-gastric dissolution conditions pertinent to immediate release dosage forms administered under fasting conditions with respect to flow rates, intra-gastric temperature profiles and gastric motility. The concept of the dynamic open flow through test apparatus has been tested using five different types of hard capsules: conventional hard gelatin capsules (HGC), three hypromellose based capsules (Vcaps, Vcaps Plus and DRcaps) and pullulan based capsules (Plantcaps). These were of different sizes but all contained 100mg caffeine in each formulation, adjusted to avoid buoyancy by addition of excipient. When the capsules were stressed in the apparatus under the dynamic flow conditions applying mild pressure simulating gastric motility, release from release from Vcaps Plus, Vcaps and Plantcaps capsules was very well comparable to HGC. Capsules are usually swallowed with cold water and the temperature dependency of release from gelatin was noted as a significant factor, since heat exchange in the stomach is slow.

Performance qualification of a new hypromellose capsule: part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules.

This Part I paper describes the qualification of a new high performance hypromellose (hydroxypropyl methylcellulose, HPMC) capsule shell which contains no gelling agent and is dissolution friendly. The development history and the test results for a series of quality attributes including scanning electron microscopy, hygroscopicity, machineability, weight variation, powder leakage, mechanical strength, stability, cross-linking, animal and human pharmacokinetic results are reported. Comparisons to gelatin and HPMC capsule containing carrageenan showed the new HPMC capsule is superior in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs. Specifically, the new HPMC capsule demonstrated improved weight variation, machineability and powder leakage than the HPMC capsule containing carrageenan. And the new capsule demonstrated a broader applicability than gelatin capsule for new drug development due to its inertness and compatibility for a wide range of excipients including those used for liquid fill formulations. In the second phase of qualification, disintegration and dissolution properties of the new HPMC were evaluated and reported in a Part II paper for 10 new clinical compounds with a variety of formulations optimized based on the biopharmaceutical classification system of solubility and permeability. Based on the superior performance, the new HPMC capsule is satisfactorily qualified and has since been used successfully for nearly 20 investigational new drug (IND) compounds.

In vitro and in vivo pharmacoscintigraphic evaluation of ibuprofen hypromellose and gelatin capsules.

PURPOSE: To evaluate the in vitro and in vivo characteristics of hypromellose (HPMC) capsules prepared using a gellan gum and potassium gelling system compared to conventional hard gelatin capsules. METHODS: The in vitro dissolution of ibuprofen gelatin and HPMC capsules was determined using the USP and TRIS buffers at pH 7.2. The effect of pH and composition of the media was determined using a model drug that is soluble throughout the pH range 1.2 to 7.2. In an 11 subject four-way crossover study, the gastrointestinal performance of ibuprofen gelatin and HPMC capsule formulations was evaluated using scintigraphy and pharmacokinetics following fasted and fed dosing. RESULTS: Acid conditions and the presence of K+ cations hinder HPMC capsule opening, whereas in water, dissolution is identical to that of gelatin. These effects are related to the nature of the gel network that is formed in the presence of cations. No significant difference in esophageal transit was observed. Although the in vivo opening times of HPMC capsules were longer than for their gelatin counterparts, no significant difference in the regulatory important pharmacokinetic metrics of C(max) and AUC was found between ibuprofen, gelatin and HPMC capsules. CONCLUSIONS: The in vitro performance of HPMC capsules differ from gelatin, which will require modification to dissolution testing methodology for certain drugs. However, for the class II BCS drug ibuprofen, the two capsule types were not statistically different when comparing AUC and C(max) values, which suggests that the in vitro differences have reduced in vivo relevance.