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
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/4207 |
| Date | January 1985 |
| Creators | Al-Meshal, Mohammed A.S. |
| Contributors | York, Peter |
| Publisher | University of Bradford, Postgraduate School of Studies in Pharmacy |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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