The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H.P.M.C.) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The δ-form, the commercially available stable form and the α and β metastable forms (nomenclature after Muller, 1978) were isolated. The α form was found to be unstable on storage. A 2 fold increase in intrinsic dissolution rate was observed for the metastable β-polymorph compared with the stable δ-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H.P.M.C. and poloxamer 188, were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H.P.M.C. was found to form a "high energy" complex with phenylbutazone which melted 10°C lower than the parent drug. When prepared by spray drying H.P.M.C. inhibited the formation of the metastable β-polymorph of phenylbutazone. A 2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex with phenylbutazone and unlike H.P.M.C. did not inhibit the formation of the β-polymorph. For both crystallised and spray dried samples a 3 fold increase in dissolution rate was obtained at polymer levels of 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of selected phenylbutazone:polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compaction of phenylbutazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (δ-form), samples of spray dried phenylbutazone (β-form) and samples containing different concentrations of H.P.M.C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H.P.M.C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H.P.M.C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H.P.M.C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples.

The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H. P. M. C. ) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The 6-form, the cammerdiallý 4- available stable ýorm and the a and s metastable forr. s (nomenclature after Huller, 1978).. were isolated. The a form was found to be unstable on storage. A .7 fold increase in intrinsic dissolution rate was observed for the metastable s-polymorph compared with the stable 6-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H. P. M. C. and poloxamer 188 were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H. P. M. C. was f8und to form a "high energy" complex with phenylbutazone which melted 10 C lower than the parent drug. When prepared by spray drying H. P. M. C. inhibited the formation of the metastable a-polymorph of phenylbutazone. A2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex witý phenylbutazone and unlike H. P. M. C. did not inhibit thejgr gation of the a-polymorph. For both crystallised and spray fo0ld increase in dissolution rate was obtained at polymer levels oý 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of-selected phenylbutazone: polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compact. ion of phenylbu. tazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (67form), samples of spray dried phenylbutazone (a-form) and samples containing different concentrations of H. P. M. C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H. P. M. C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H. P. M. C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H. P. M. C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples. / Saudi Arabian Government