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Abstract
absorption of many drugs. Failure to meet the dissolution requirements may lead to poor absorption and hence critical therapeutic problems. Several papers describe the problem of fulfilling the dissolution profiles of commercial products which may lead to serious problems. Dissolution problems result from poor solubility of the active ingredient in the dissolution conditions.
The work in this thesis was directed to enhance the dissolution of a benzodiazepine tablet clonazepam. The work was divided into the following chapters:
Chapter 1: Formulation And Evaluation Of Clonazepam 2 Mg Tablets Using Water Soluble Carriers And Other Dissolution Enhancers.
The objective of this chapter was to formulate clonazepam as a solid dispersion by using different water soluble carriers such as polyethylene glycol 6000 and povidone K 30. The prepared solid dispersions were subjected to DSC thermal analysis and dissolution studies. These prepared solid dispersions were then incorporated into tablets. The prepared tablets were then subjected to the following tests: uniformity of weight, content uniformity, disintegration time, resistance to crushing of tablets, friability and dissolution.
The following conclusions were obtained:
1. No chemical incompatibilities exist between clonazepam and each of polyethylene glycol 6000 and povidone K 30, so that these two excipients can be incorporated as carriers during solid dispersion preparation.
2. The dissolution of clonazepam from the formed aggregates was little enhanced due to incorporation of lactose or microcrystalline cellulose pH 102.
However, these trials did not give the desired increase in dissolution results. Wet granulation technique using polyethylene glycol 6000 (1 gm) dissolved in acetone (33 ml) where the ratio of clonazepam: PEG 6000 was 1:1 has been done and this technique has produced tablets with very acceptable dissolution results according to USP 27 and has been scaled up for three successive production batches. These three batches have also been subjected to stability study conditions at both accelerated and long term conditions.
But upon publication of USP 30; dissolution parameters have been changed from 1000 ml water at 100 r.p.m for 60 minutes to 900 ml water at 75 r.p.m for 45 minutes. The conforming clonazepam 2 mg tablets according to USP 27 have been re-analyzed according to USP 30 dissolution parameters. It was found that these tablets are not conforming to specifications of USP 30. Therefore; many trials with different ideas have been recently done in order to produce tablets conforming to dissolution specifications.
Wet granulation technique using polyethylene glycol 6000 (1 gm) dissolved in acetone (either 50 ml or 100 ml) has also been done where the ratio of clonazepam: PEG 6000 was 1:1.
Different clonazepam: PEG 6000 ratios 1:2, 1:3, 1:5, 1:7 and 1: 9 have been used by dissolving clonazepam and PEG 6000 in acetone 33 ml and have been incorporated into tablets.
Clonazepam: PEG 4000 ratio 1:1 and clonazepam: PEG 35000 ratio 1:1 have also been used by dissolving clonazepam and PEG 4000 or PEG 35000 in acetone 33 ml and have been incorporated into tablets.
Other dissolution enhancers such as poloxamer 407, Sodium lauryl sulphate, sodium docusate have also been used.
Povidone K 30 was used at concentration from 3 % to 6 % w/w and it was found that using povidone K 30 at a concentration 6 % w/w gives very acceptable dissolution results if compared with the previous dissolution enhancers.
Effect of using two solvents into the preparation of clonazepam 2 mg tablets (acetone for clonazepam and ethyl alcohol 95 %) was investigated and it was found that this technique produces the most acceptable dissolution results.
Chapter 2: Formulation And Evaluation Of Clonazepam 2 Mg Tablets Prepared By Solid Dispersion Technique Using Cyclo-dextrins As Carriers.
The incorporation of clonazepam in a cyclodextrin carrier by solvent evaporation method or kneading method may result in an enhancement in its dissolution rate. In this prospect, solid dispersions of clonazepam containing either ß-cyclodextrin or hydroxypropyl ß-cyclodextrin were prepared in an attempt to improve its solubility and dissolution rate. Solubility of clonazepam in presence of each carrier was studied.
The prepared solid dispersions were subjected to DSC thermal analysis and in-vitro dissolution study. These prepared solid dispersions were then incorporated into tablets. The prepared tablets were subjected to the following tests: Uniformity of weight, content uniformity, disintegration time, resistance to crushing of tablets, friability and in-vitro dissolution. The following conclusions were obtained:
1. The yielded tablets had a smooth surface with no sticking and were; non –friable, disintegrable (by erosion pathway).
2. The solvent evaporation method using ß-cyclodextrin can produce clonazepam solid dispersion which can be incorporated into tablets with enhanced dissolution profile if compared with that prepared using hydroxypropyl ß-cyclodextrin by solvent evaporation method.
3. The kneading method using either ß-cyclodextrin or hydroxyl-propyl ß-cyclodextrin can produce clonazepam solid dispersion which can be incorporated into tablets but with no enhanced dissolution profile.
Chapter 3: Scaling Up Of Clonazepam 2 Mg Tablets.
The objective of this chapter was to scale up (according to USP 27) clonazepam 2 mg tablet formulation from lab scale (500 tablets) to full production scale (500,000 tablets).
The following could be concluded:
a. Clonazepam 2 mg tablets could be produced in a design that could be scaled successfully from lab scale to full production scale with no problems.
b. Production scale trial was performed at scale 500,000 tablets using high shear granulator.
c. This technique has been done for three successive production batches. The resulting tablets from these batches were withdrawn at start, middle and end of compression process and were subjected to the following tests: Uniformity of weight, content uniformity, disintegration time, resistance to crushing of tablets, friability and in-vitro dissolution.
d. All the results of these tests were conforming to specifications and indicated that scaling up process has been done successfully.
Chapter 4: Stability Of Clonazepam 2 Mg Tablets
The objective of this chapter was to apply both accelerated and long term stability protocols to follow up the three scaled up production batches. The following conclusions were obtained:
a. Accelerated stability study shows that tablets kept at stability conditions 40°C/75% have uniformity of weight, content uniformity, disintegration time, resistance to crushing of tablets, friability and dissolution results conforming to specifications.
b. Long term stability study shows that tablets kept at stability conditions 25°C/60% have uniformity of weight, content uniformity, disintegration time, resistance to crushing of tablets, friability and dissolution results conforming to specifications till the end of the shelf life of the product.