• Characterization of beta-cyclodextrin for direct compression tableting.

      Pande, Girish Shridhar; Shangraw, Ralph F., Ph.D. (1993)
      A physically modified beta-cyclodextrin sample (BCD-DC) was characterized as a filler-binder for direct compression tableting by comparing it to a commercially available beta-cyclodextrin product (Kleptose{dollar}\sp\circler{dollar}) and commonly used direct compression filler-binders such as microcrystalline cellulose (MCC), spray dried lactose (SDL) and dicalcium phosphate (DCP). Aspects examined included the compactibility of beta-cyclodextrin, deformation mechanism of beta-cyclodextrin, the role of moisture in the compactibility of beta-cyclodextrin and the effect of beta-cyclodextrin on the dissolution of poorly soluble actives. The physical modification of beta-cyclodextrin resulted in a considerable improvement in its properties as a direct compression filler-binder. The compactibility of the BCD-DC sample was comparable to that of MCC and significantly better than Kleptose{dollar}\sp\circler{dollar}, SDL and DCP. BCD-DC possessed adequate flow for direct compression using a rotary press. The primary deformation mechanism of BCD was found to be plastic flow. Scanning electron photomicrographs of BCD-DC showed the presence of cracks and laminations which result in the higher surface area of BCD-DC relative to Kleptose{dollar}\sp\circler{dollar}. These differences in the external particle characteristics are primarily responsible for the greater compactibility of BCD-DC. Moisture plays a critical role in the compactibility of beta-cyclodextrin. The moisture sorption-desorption isotherms revealed considerable hysteresis. The complete removal of water results in a loss of the compactibility of beta-cyclodextrin. There appears to be an optimal level of moisture for maximum compactibility. The dissolution studies using direct compression formulations of spironolactone revealed that dissolution rate of the drug was significantly faster from a formulation containing beta-cyclodextrin as a filler than from those containing MCC, SDL, or DCP as the fillers. This can be attributed to the increased solubility of spironolactone due to complexation with beta-cyclodextrin. The beta-cyclodextrin formulation was more compactible than the SDL and DCP formulations but less than the MCC formulation. For the medroxyprogesterone acetate formulations, dissolution rate was fastest from the formulation containing SDL as the filler followed by the beta-cyclodextrin formulation. This was attributed to the higher solubility of SDL and lack of interaction with beta-cyclodextrin. beta-Cyclodextrin has been characterized more than any other modern tablet excipient prior to commercialization and has considerable promise as a direct compression filler-binder.
    • Formulation and manufacturing of tablets for instantaneous preparation of sustained release suspensions

      Habib, Yacoub Suhail; Shangraw, Ralph F., Ph.D. (1996)
      A novel solid oral dosage form, a tablet which can disintegrate rapidly in water to form homogenous suspension of high viscosity to deliver sustained release medication was developed. Such a system avoids the administration of large doses of drugs at one time and circumvents the stability problems encountered when sustained release coated pellets are incorporated in a suspending vehicle. The key to the dosage form is a rapidly disintegrating tablet followed quickly by the development of a viscous suspension system. By design, the viscous gel does not form until disintegration of the tablet is complete. The system contains a processed swellable material, composed of carbomer produced by extrusion-spheronisation which is able to generate viscosity on contact with water, an active drug substance exhibiting sustained release properties from polymethacrylate copolymer coated beads, and freeze-dried cushioning beads composed of microcrystalline cellulose (MCC) and croscarmellose sodium. The cushioning beads, produced by extrusion-spheronisation, possess certain properties among which are compactibility and the capability of disintegrating rapidly. The incorporation of carbomer as a fine powder impedes the disintegration process due to the networking of the carbomer in the tablet matrix and at the surface which upon hydration results in a voluminous mass. However, processing of the viscosity enhancer into beads produced by either extrusion-spheronisation with microcrystalline cellulose (MCC) using a hydroalcoholic system or powder layering onto sugar spheres using alcoholic PVP as a binder provided a solution to the problem. Freeze-drying the cushioning beads containing MCC and croscarmellose sodium produced beads which possessed high compactibility and the ability to maintain good content uniformity and weight variation (less than 5%) when mixed with the drug-loaded membrane-coated beads. The cushioning beads exhibited initial fragmentation into primary powder particles followed by plastic deformation during compaction with the drug-loaded membrane-coated millispheres. They were able to not only to fill the voids between the drug-loaded millispheres but also to surround them so that the tablet was held together by excipient-excipient contact. Moreover, the compacts formed from those cushioning beads were able to disintegrate rapidly and release intact drug-loaded beads with minimal effect on drug release kinetics. Compression force, percentage of drug-loaded membrane-coated beads and the type of membrane coating were important factors affecting the release profile of the tablet compacts. Unlike ethylcellulose, polymethacrylate copolymer coatings were able to resist the mechanical stresses of compaction with relatively small changes in drug release profiles. The increase in the percentage of drug released from the tablets containing 12.5% sustained release theophylline beads in freeze-dried cushioning beads compacted at a pressure of 332 Kg/cm2 relative to the uncompacted beads was 20, 21, 19, 16, 10, 7, 4 and 2% at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours, respectively. This increase in the drug release was attributed to the fracturing of the membrane-coated beads present at the tablet surface. The formulation of tablets for instantaneous preparation of sustained release suspension was achieved by compressing a blend composed of 8.3% drug-loaded beads coated with polymethacrylates, 16.7% carbomer beads produced by extrusion-spheronisation and the freeze-dried cushioning beads. These tablets disintegrated quickly in water forming a homeogenous suspension after stirring for 1-1.5 minutes.