الفهرس 
صفحة العنوانOnly 14 pages are availabe for public view
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Abstract
Oral route considered as the most abundant route of administration, however, several challenges affect oral bioavailability including; the most frequently occurring is the drug poor aqueous solubility, which is also the dissolution rate-limiting step, thus solubility is considered a vital factor for the bioavailability enhancement of poorly water soluble drugs BCS class II, IV.
Schizophrenia is a lifelong disorder, affecting the ability of an individual to live a normal life. It is also associated with suicide to almost 10% of patients. Treatment goals involve the control of the positive psychotic symptoms including hallucinations, and the negative symptoms including apathy and hostility and sleep disturbances, other cognitive impairments require longer periods of treatment.
Clozapine (CLZ) a second-generation antipsychotic demonstrated a superior efficacy for the treatment of patients with resistant schizophrenia, and with suicidal tendencies. However it is reserved as a second line treatment due to unusual side effect profile, life threatening agranulocytosis. It is a yellow crystalline powder that is classified as class II according to BCS classification system, practically insoluble in water; and it is also hepatically metabolized, thus considered as a low bioavailable drug.
Among the methods used for the enhancement of solubility, dissolution and bioavailability is the solid dispersion technique, which results in the reduction of particle size with better porosity, wettability, and surface area available for dissolution. Most solid dispersion formulations show great enhancement in solubility however stability is a major issue, due to recrystallization or phase separation during storage.
Among the methods of preparation of solid dispersion; microwave irradiation which is stated as a viable alternative to prepare solvent-free solid dispersions with numerous advantages over the conventional methods used for the preparation of solid dispersion. Such as decreased decomposition rate due to lower thermal level of exposure and shorter duration of exposure, and without the use of organic solvents.
Chapter I: Preliminary studies for solubility enhancement of Clozapine, using microwave technique for solid dispersion preparation.
The aim of this chapter is to verify a quantitative method for the determination of CLZ, determination of the discriminative media for solubility, and dissolution evaluation. Assessment of the compatibility of CLZ with different polymers, choosing the optimum polymers for the preparation of CLZ solid dispersion using microwave assisted fusion technique.
Results showed that CLZ can be determined using HPLC with the verification of the used Pharmacopeial method, for the following parameters: linearity ranged from 10 to 300 µg/ml, inter-day accuracy and precision showed acceptable results, with recovery (99.46-99.94%). Also CLZ can be determined using UV spectrophotometer, with linearity ranging from 5 to 30µg/ml. The stability of CLZ to the microwave radiation was proved with recovery (99.905 %).
Compatibility of CLZ with chosen polymers (Sodium Carboxymethyl Cellulose (CMC-Na), Pluronic F-68, Hydroxypropyl methylcellulose -HPMC E5, Polyvinyl Alcohol (PVA), Polyvinyl pyrrolidone (PVP K-30), Gelatin, Poly Ethylene Glycol 6000 distearate (PEG 6000 DS) was assessed using Fourier Transform infra-red spectroscopy, the IR spectra revealed the absence of chemical interaction with no deterioration of CLZ major peaks was observed.
CLZ dose solubility volume measurement was determined in different media, water was chosen as the discriminating medium for the assessment of solubility and dissolution of CLZ and formulations, since it had the highest dose solubility volume.