Physicochemical and tableting properties of crystallised and spray-dried phenylbutazone containing polymeric additives. Effect of polymeric additives (hydroxypropyl methylcellulose and a polyoxyethylene-polyoxypropylene glycol) on the crystalline structure, physicochemical properties and tableting behaviour of crystallised and spray-dried phenylbutazone powders

摘要

The physicochemical properties of a drug affect to a large extentudits subsequent biological absorption and bioavailability profile.udConsiderable pharmaceutical interest is therefore directed torwards theudimprovement of drug dissolution characteristics of drugs with lowudaqueous solubility.udThis thesis has considered the controlled modification of druguddissolution profiles by means of incorporating low concentrations ofudhydrophilic polymers by different processes into a host drug substance.udIn order to examine this approach and its potential use, the physicochemical,udsolid state, stability and tableting properties of a poorlyudaqueous soluble drug, phenylbutazone, in alternative polymorphic formudand containing low levels of two hydrophilic polymers - hydroxypropyludmethylcellulose (H. P. M. C. ) and the surfactant poloxamer 188 - prepared byudboth conventional crystallisation and spray drying are reported.udAs an integral nart of the work attempts were mado to identify theuddifferent polymorphic forms of phenylbutazone. The 6-form, the cammerdiallýud4- available stable ýorm and the a and s metastable forr. s (nomenclature afterudHuller, 1978).. were isolated. The a form was found to be unstable onudstorage. A .7 fold increase in intrinsic dissolution rate was observed forudthe metastable s-polymorph compared with the stable 6-polymorphic form.udThe effect of crystallisation rate on the formation of polymorphs ofudphenylbutazone was studied using a mini-spray dryer, and slower rates ofudcrystallisation were found to favour polymorph formation.udThe hydrophilic polymers, H. P. M. C. and poloxamer 188 were incorporatedudby conventional crystallisation and spray drying into the drug crystal.udSamples were subjected to a series of tests including differentialudscanning calorimetry, X-ray powder diffraction, scanning electron microscopy,udand intrinsic dissolution and solubility. When prepared byudconventional crystallisation H. P. M. C. was f8und to form a "high energy"udcomplex with phenylbutazone which melted 10 C lower than the parent drug.udWhen prepared by spray drying H. P. M. C. inhibited the formation of theudmetastable a-polymorph of phenylbutazone. A2 fold increase in intrinsicuddissolution rate was observed for crystallised and spray dried samplesudcontaining 2% w/w or more added polymer.udPoloxamer 188 did not form a complex witý phenylbutazone and unlikeudH. P. M. C. did not inhibit thejgr gation of the a-polymorph. For bothudcrystallised and spray fo0ld increase in dissolution rate wasudobtained at polymer levels oý 1% w/w or above. The increase in dissolutionudhas been attributed to facilitated wetting by lowering of interfacialudtension rather than through the formation of micelles.udThe stability of-selected phenylbutazone: polymer samples was tested atudelevated temperatures. The stability was found to be affected both by theudmethod of sample preparation and the type of additive. Large breakdownsudoccurring by a hydrolytic effect were identified for the crystallised phenylbutazoneudsamples containing poloxamer 188.udThe effects on compact. ion of phenylbu. tazone in alternative formudand presence of polymeric additives were studied by compressing samples ofudsimilar particle sizes of phenylbutazone as supplied (67form), samples ofudspray dried phenylbutazone (a-form) and samples containing differentudconcentrations of H. P. M. C. prepared both by conventional crystallisationudand spray drying. Compaction data were analysed according to the Heckeludrelationship and by force transmission ratio as well as from the tensileudstrengths of prepared tablets.udThe presence of H. P. M. C. up to 5% w/w concentration in phenylbutazoneuddid not change the mean yield pressure for the crystallised or sprayuddried samples, although a difference in mean value was observed betweenudthe crystallised and spray dried materials, 93.22 MPa and 147.02 MPaudrespectively. Force transmission was found to be improved for samplesudcontaining H. P. M. C. prepared by both techniques and in general, theudtablet tensile strengths for crystallised samples containing H. P. M. C.udwere approximately three times greater than for spray dried samples atudequivalent tablet porosity. Differences are attributed to variation inudsolid state and particulate properties between samples.