FORMULATION AND EVALUATION OF TRIHEXYPHENIDYL HYDROCHLORIDE TABLTES

Transcription

1 301 P a g e International Standard Serial Number (ISSN): International Journal of Universal Pharmacy and Bio Sciences 2(6): November-December 2013 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89*** ICV 5.13*** Pharmaceutical Sciences RESEARCH ARTICLE!!! FORMULATION AND EVALUATION OF TRIHEXYPHENIDYL HYDROCHLORIDE TABLTES Rajesh Akki 1*, P V Ayodhya Neelima 1, N Vijaya lakshmi 1, K Manasa 1, Munagala Gayatri Ramya 2 1 Hindu College of Pharmacy, Amaravathi Road, Guntur University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur KEYWORDS: Trihexyphenidyl, optimization and process parameters, Preformulation studies. For Correspondence: Rajesh Akki * Address: Department Of Pharmaceutics, Hindu College of Pharmacy, Guntur ABSTRACT The study was undertaken with an aim to formulate antiparkinson agent on oral drug delivery. The selected antiparkinson agent was Trihexyphenidyl hydrochloride. The active pharmaceutical ingredient of Trihexyphenidyl hydrochloride was selected and formulated as immediate release of oral conventional tablets of 2mg.Preformulation studies were carried and the results were found to be satisfactory. Experimental started with the process variables such as Bulk density, Angle of repose, and Compressibility index of the API. The compatible excipients were selected for formulation development. The content uniformity, Assay, and dissolution profile of Trihexyphenidyl formulation was compared with the Innovator s product. Binder variation study, disintigrant variation study and lubricant variation study was performed..however further formulation development involves optimization and process parameters. In present work direct compression were employed to prepare tablets. Microcrystalline cellulose and Pharmatose DCL21 is used as diluents. Pregelatinised starch, corn starch and sodium starch glycolate are selected as disintegrants. Tablets are compressed using 8mm flat punches with Rimek mini press II, a 12 station rotary compression machine. Post compression parameters hardness, friability, weight variation, disintegration time, wetting time, content uniformity and dissolution studies are studied. The developed trails were tested for in-vitro dissolution profile and compared with the reference product of trihexyphenidyl-2 from Watson laboratories.

2 P a g e International Standard Serial Number (ISSN): INTRODUCTION: Trihexyphenidyl (Artane, Apo-Trihex, Parkin, Pacitane), also known as benzhexol, is an antiparkinsonian agent of the antimuscarinic class. It has been in clinical usage for decades. The drug is available as the hydrochloride salt. Trihexyphenidyl is used for the symptomatic treatment of Parkinson's disease in mono- and combination therapy. It is active in postencephalitic, arteriosclerotic, and idiopathic forms. The drug is also commonly used to treat extrapyramidal side effects occurring during antipsychotic treatment. It reduces the frequency and duration of oculogyric crises as well as of dyskinetic movements and spastic contractions. Excessive salivation may also respond. Trihexyphenidyl may improve psychotic depression and mental inertia frequently associated with Parkinson's disease and symptomatic problems caused by antipsychotic treatment. The drug cannot cure Parkinson's disease, but may provide substantial alleviation of symptoms. An estimated 50 to 75% of patients with Parkinson's disease will react positively and experience a 20 to 30% symptomatic improvement. To increase therapeutic activity trihexyphenidyl is often given concomitantly with levodopa, other antimuscarinic or antihistaminic (e.g. diphenhydramine) agents. Combination treatment with dopaminergic agonists such as cabergoline is also possible. This is often termed a 'multidimensional approach'.it has also been prescribed for Essential Tremors. Direct compression method is selected upon several trails at last formula was optimized. During development of formula in process tests such as LOD, Bulk density, Tapped density, Compressibility index and Hausner s ratio were evaluated for granules and weight variation, hardness, thickness, disintegration were evaluated for the core tablets. Finished products were evaluated for Disintegration, content uniformity Assay, Related substances and dissolution.trihexyphenidyl hydrochloride was selected and formulated as immediate release of oral conventional tablets of 2mg.The objective of the present study is as follows:- Preformulation Studies, Formulation of Oral conventional tablet of Trihexyphenidyl hydrochloride by Wet Granulation and Direct Compression method. Evaluation of tablets for their Physical parameters, Drug Content, Disintegrating time, Assay, content uniformity and Dissolution Rate. Selection of formulation based on the Evaluation. Evaluation of Marketed formulation. Comparison of optimized formulation and Marketed formulation. MATERIALS AND METHODS: Trihexyphenidyl hydrochloride was a gift sample from Natco pharma, Hyderabad. All other chemicals and excepients were purchased from Local Market. S.no. Angle of repose (θ) Table: 1 PREFORMULATION STUDIES OF DRUG Compressibility Index (%) Hausner s ratio Bulk density Tap density

3 P a g e International Standard Serial Number (ISSN): TABLE: 2 SOLUBILITY STUDIES.% of Solubility Time ph4.5aceate buffer ph 6.8 phophate buffer 0.1N HCl Water intervals (min) Average Average average Average Drug-Excipient Compatibility studies Drug is in intimate contact with one or more excipients in all the dosage forms. Later it could affect the stability of drug. Knowledge of drug-excipients interaction is useful in selecting an appropriate excipient. Drug and excipients are stored at 55 for 14 days, 40 C at RH 75% for 14days, 28 days. After 14, 28 days they are subjected for analysis of description, assay, LOD, purity. TABLE 3: DRUG EXCIPIENT COMPATIBILITY TEMPERATURE AND HUMDITY % RH DAYS 0 TH 14 TH 7 TH 14 TH 28 TH Excipients Ratio Description S.No Initial Final 1 API 1 BLD BLD 2 MCC (ph 101) 1 BLD BLD 3 MCC (ph 102) 1 BLD BLD 4 Povidone USP(PVPK-30) 1 BLD BLD 5 HPMC E5 1 BLD BLD 6 Corn starch 1 BLD BLD 7 Pre gelatinised starch 1 BLD BLD 8 Sodium starch glycolate 1 BLD BLD 9 1 BLD BLD 10 Stearic acid 1 BLD BLD 11 Colloidal silicon dioxide 1 BLD BLD 12 API + Avicel(ph101) 1:10 BLD BLD 13 API + Avicel(ph102) 1:10 BLD BLD 14 API + Povidone usp(k-30) 1:5 BLD BLD 15 API + HPMC E5 1:5 BLD BLD 16 API + Cornstarch 1:5 BLD BLD 17 API + SSG 1:5 BLD BLD 18 API + PGS 1:5 BLD BLD 19 API + 1:0.5 BLD BLD 20 API + Stearic acid 1:0.5 BLD BLD 21 API + colloidal silicon dioxide 1:0.5 BLD BLD BLD Below limit of detectable

4 P a g e International Standard Serial Number (ISSN): Preparation of tablets using direct compression method Table:4 Formulations: S.No Ingredients F1 F2 F3 F4 F5 F6 F7 1 THP Pharmatose DCL Avicel ph Corn starch Pre gelatinized starch Sodium Starch Glycolate Aerosil Magnesium Stearate Total S.No Ingredients F8 F9 F10 F11 F12 F13 F14 1 Trihexy phenidyl hydro chloride Avicel ph sodium starch glycolate Total TABLE 5: DIRECT COMPRESSION BATCH PROCEDURES: S.No Step1 Weigh and Mix ingredients After passing through 40# mesh Step2 Addition of ingredients to blend After passing through 40# mesh Dry mix blending time And instrument used for blending Addition of lubricants To the dry mix which is already passed through mesh Lubricati on Blending time F1 API+DCL 21+Avicel PH 102+PGS min Aerosil + 40# 2 min F2 API+DCL 21+Avicel PH corn starch+ssg min Aerosil + 40# 2 min F3 102+SSG min 40# 2 min F4 Avicel PH SSG (Mix for 10 min) API Double cone blender,15 min 60# 3 min

5 F P a g e International Standard Serial Number (ISSN): Avicel PH SSG (Mix for 10 min) API Double cone blender 15 min 60# 3 min F Double cone blender 15 min 60# 5 min F Double cone blender 10,15,20 min(10+5+5min) 60# 5 min F Double cone blender 10 MIN 60# 5 min F Double cone blender 10 MIN 60# 5 min F Double cone blender 10 MIN 60# 5 min F Double cone blender 10 MIN 60# 5 min F12 F13 F Conta bin blender 18,20, Conta bin blender 16,18,20 min (16+2+2) Conta bin blender 18,20,22 In all the above formulations geometrical mixing was done TABLE 6: PHYSICAL PROPERTIES OF TABLETS 40# 40# 40# 2,3,5 min (2+1+2) 2 min 2,3 min Formulations Average Thickness Hardness Disintegration Friability weight(mg) (mm) kps (sec) (%) F F F F F F F F F F F F F F

6 P a g e International Standard Serial Number (ISSN): Different hardness F5 TABLE: 7 EFFECT OF HARDNESS USING F5 FORMULATION EVALUATION OF TABLETS Breakability test in tablets: To define the procedure for Breakability test for Trihexyphenidyl HCl 2&5 mg. Breakability test is applied on tablets with single or multiple score lines, to find out the influence of breakability methodology on uniformity of weight. The test is applied to confirm that the subdivided parts of a tablet comply with the requirements for uniformity of weight. Acceptance criteria: Not more than two of the individual weights, out of 20 tablets, deviate from the average weight by ± 10 % and none deviate by ± 20.0%. MOISTURE PICK UP STUDIES To carry out moisture pick up studies or hygroscopic studies of API, blend, finished product. 25 C Temp/Humidity 29% RH Description 43% RH 75%RH Average weight mg TABLE: 8 MOISTURE PICK UP STUDIES Observation Lubricated (API) after 168 hours Blend % Moisture pick up (maximum) Thickness (mm) Off White color powder Hardness kps Off white powder. Disintegration (sec) Core tablets White colored round shaped tablets debossed with N and T on either side of score line and 2 on lower side.. NIL % NIL Friability (%) Description complies complies complies % Moisture pick up (maximum) NIL NIL NIL Description complies complies complies % Moisture pick up (maximum) % 0.06% %

7 % OF DRUG RELEASE P a g e International Standard Serial Number (ISSN): Table : 9 DISSOLUTION PROFILE AT DIFFERENT HARDNESS Time(min) % Drug release at different Hardness 3kps 3-5kps 5-8kps 8-10kps % % EFFECT OF HARDNESS TIME IN MIN 3 3 to 5 5 to 8 8 to 10 FIGURE: 2 EFFECT OF HARDNESS Table 10 Dissolution profile Results from F1 to F7 Sampling Time Percentage of drug release F1 F2 F3 F4 F5 F6 F

8 % OF DRUG RELEASED % DRUG RELEASED P a g e International Standard Serial Number (ISSN): TABLE 11: DISSOLUTION PROFILE RESULTS FROM F8 TO F14 Sampling Percentage Of Drug Release Time F8 F9 F10 F11 F12 F13 F % DRUG RELEASED F1 F2 F3 F4 F TIME Figure: 3 PERCENTAGE DRUG RELEASE F1 TO F5 120 % DRUG RELEASED TIME F6 F7 F8 F9 F10 Figure: 4 PERCENTAGE DRUG RELEASE F6 TO F10

9 % OF DRUG RELEASED P a g e International Standard Serial Number (ISSN): % DRUG RELEASED TIME F11 F12 F13 F14 Figure: 5 PERCENTAGE DRUG RELEASE F11 TO F14 Table 12: Results of Content Uniformity and Assay Formulations Content uniformity of blend 10 samples minimum Maximum Blend Assay C.U of tablets Assay of tablets F F F F F F F F F F F F F F

10 % OF DRUG RELEASE P a g e International Standard Serial Number (ISSN): Table 13: STABILITY DATA S.No CHARACTERISTICS TESTED 1 Description INITIAL I st MONTH II nd MONTH III rd MONTH White colored round shaped tablets debossed with N and T on either side of score line and 2 on lower side. Complies Complies Complies 2 Average Weight (in mg) mg Water content (%w/w) % 4 Dissolution (By HPLC) 102.5% % Assay (By HPLC) 101.3% % 99.7% Related substances Unknown impurity-total Unknown impurity-max TABLE: 14 PERCENTAGE OF DRUG RELEASE (STABILITY DATA) Sampling Time Percentage Of Drug Release 30 days 60 days 90 days STABILITY DATA TIME IN MIN Percentage Of Drug Release 30 days Percentage Of Drug Release 60 days Percentage Of Drug Release 90 days Figure: 6 PERCENTAGE DRUG RELEASE

11 P a g e International Standard Serial Number (ISSN): Table 15: Breakability test S.No T.w(mg) R1 L Min Max Avg T.W: Total Weight, R1: Right side half tablet, L1: Left side Half tablet. Not more than two of the individual weights, out of 20 tablets, deviate from the average weight by ± 10 % and none deviates by ± 20%.so here breakability test is passed. Table 16: Blending time optimization dry mix based on Content uniformity F12 F13 18MIN 20MIN 22MIN 16MIN 18MIN 20MIN Avg

12 %OF DRUG RELEASED P a g e International Standard Serial Number (ISSN): Table 17: BLENDING TIME OPTIMIZATION OF BLEND AFTER LUBRICATION BASED ON CONTENT UNIFORMITY F 12 F13 2MIN 3MIN 5MIN 2min Avg INNOVATOR DETAILS Trihexyphenidyl Hydrochloride Tablets, USP 2 mg are 10/32", scored, round, white, flat faced, tablets imprinted DAN DAN and 5335 supplied in bottles of 100 and Dispense in a tight container with child-resistant closure.store at C (68-77 F). WatsonLaboratoriesInc. Corona, CA USA Table : 18 LOTNUMBER L6E0619 Hardness Thickness Weight content Disintegration time Moisture kps 2..5 mm 180 mg sec 3.6% % DRUG RELEASED TIME INNOVATOR F14 Figure: 7 Percentage Drug Release Of Comparing With Innovator Product

13 P a g e International Standard Serial Number (ISSN): TABLE:19 PERCENTAGE DRUG RELEASE OF INNOVATOR SAMPLE AND F14 %Drug release Time Innovator F RESULTS AND DISCUSSION The present investigation was undertaken to formulate Trihexy phenydyl hydrochloride used for the treatment of Parkinson s disease.direct compression techniques were used in formulating the drug into oral conventional tablet. As per the above data solubility is more in ph 4.5 buffers is better than the other ph 6.8 buffer and water, 0.1NHCL. Drug excipient compatability all are in below the limit. All the experimental formulation batches have been subjected to various evaluations.viz, average weight, friability, disintegration, thickness, hardness, dissolution, content uniformity.f1 to F 14 were carried out by Direct Compression method.in formulation F1 Pharmatose DCL concentrations is decreased to 32.66%; MCC concentration is increased to 60% and Pregelatinised starch 5% is used for 150mg tablet. DT was found to be 55 seconds; % drug release 94.7%. Assay and content uniformity are not achieved.in formulation F2 Pregelatinised starch is replaced with SSG 3.33% and Corn starch 3.61% is used. Content uniformity and assay values are not achieved.in formulation F3, Pharmatose DCL and Corn starch are removed. Increased the concentration of Avicel PH102 to 91.66%; SSG 6% is used. DT was found to be 30 seconds, % drug release is 97%. Content uniformity and assay results are better than previous formulation.in formulation F4 method of preparation changes. Blending is done at 2 stages with geometrical mixing.. (i) Avicel PH SSG for 10minutes. (ii) API for 15 minutes.content uniformity and assay are better. But dissolution does not match with the innovator. Formulation F5 was conducted to study the effect of hardness. There is no effect of hardness on DT and dissolution. Formulation F6 was carried out with new API. Blending time is 15 minutes. %drug release is 92.68%. Content uniformity and assay results failed. Formulation F7 was carried out to check the content uniformity by changing the blending time 10, 15, 20 minutes. At 10 and 15 minutes content uniformity and assay achieve better results. FORMULATION F8 TO F11 WAS CARRIED OUT TO STUDY THE EFFECT OF EXCIPIENTS. Formulation F8 was done to study the effect of 4% SSG. Here the result shows that there is no effect on DT and Dissolution. Formulation F9 was done to study the effect of 8% SSG. Here the result shows that there is no effect on DT and Dissolution. Formulation F10 was done to study the effect of

14 P a g e International Standard Serial Number (ISSN): % magnesium stearate. Here the result shows that there is no effect on DT and Dissolution. Formulation F11 was done to study the effect of 1.5% magnesium stearate. Here the result shows that there is no effect on DT and Dissolution. BLENDING TIME OPTIMIZATION BEFORE AND AFTER LUBRICATION F12 TO F13 In formulation F12, batch size was increased, so occupancy of blend also increases, this may show effect on content uniformity. In this case blending time is studied at 18, 20, 22 minutes. After lubrication 2, 3, 5 minutes blending is done. For 18 minutes, results are good. Formulation F13 was carried out to check and optimize the parameters. Here blending time is studied at 16, 18, 20 minutes. For 18 minutes results are good. So 18 min blending time is optimized. OPTIMIZED FORMULA In formulation F14 blending are done for 18 minutes. Content uniformity and assay results are good. % drug release matches with innovator. All parameters match with innovator. This is the optimized formulation. CONCLUSION The active pharmaceutical ingredient of Trihexyphenidyl hydrochloride was selected and formulated as immediate release of oral conventional tablets of 2mg.Preformulation studies were carried and the results were found to be satisfactory. The compatible excipients were selected for formulation development. The oral route of drug administration is the most important method of administering drugs for systemic effects. The content uniformity, Assay, and dissolution profile of Trihexyphenidyl formulation was compared with the Innovator s product. Binder variation study, disintigrant variation study and lubricant variation study was performed. However further formulation development involves optimization and process parameters.post compression parameters hardness, friability, weight variation, disintegration time, wetting time, content uniformity and dissolution studies are studied. Tablets containing pregelatinised starch, corn starch showed disintegration time which are not satisfactory than the tablets containing sodium starch glycolate. Micro crystalline cellulose PH 102 used in direct compression since it is free flowing powder. Content uniformity, Assay, disintegration time and percentage drug release of optimized formulation F-13 and F-14 are mostly matched with marketed product. Direct compression method is selected upon several trails at last formula was optimized. Finished products were evaluated for Disintegration, content uniformity Assay, Related substances and dissolution. The developed trails were tested for in-vitro dissolution profile and compared with the reference product of trihexyphenidyl-2 from Watson laboratories. The in-vitro dissolution of formula F14 was nearest to the reference product. In direct compression method, different

15 P a g e International Standard Serial Number (ISSN): formulation were carried out for the selection of excipients, change in concentration of excipients, method of preparation changing, changing of blending time, study on effect of hardness, effect of disintegrant, lubricant and blending time. Blending time optimization plays a major role to achieve content uniformity and Assay. At different intervals of time blending was conducted and at last optimized the blending time based on the content uniformity and assay. Impact of hardness against dissolution was performed and optimum hardness was derived. Impact of disintegrating agent sodium starch glycolate against dissolution was performed and optimum concentration of disintegrating agent was achieved. Impact of lubricant against dissolution was performed and optimum concentration of lubricant was achieved. Moisture pick up studies were performed for API, Lubricated blend, Core tablets to know the hygroscopic characters. All the results were found to be satisfactory. The optimized batch was performed stability studies at 40 C±2 C /75%±5%RH for three months. Stability samples were evaluated initially, after one month, second month and third month. The results were compared with the predetermined specifications. All the results were found to be satisfactory. Hence the designed and developed formula of Trihexyphenidyl hydrochloride tablets was stable. BIBILOGRAPHY 1. Lachman L., Liberman H. and Kanig J.; The Theory and Practice of Industrial Pharmacy; Third Edition: , Aulton M.; Pharmaceutics: The Science of Dosage Form Design; International Student Edition: , Swarbrick J. and Boylan J.; Encyclopedia of Pharmaceutical Technology; Volume 14: , , Taylor and Francis; International Journal of Toxicology: Toxicity of excipients- A food and drug administration perspective; 2003; 22(5): Chowhan Z.; Pharmaceutical Technology: Excipients and their functionality in drug product development; 1993; (9). 6. Lachman L., Liberman L. and Schwartz J.; Pharmaceutical Dosage Forms: Tablets; Second Edition : Volume I. 7. Banker G. and Rhodes C.; Drug and Pharmaceutical Sciences: Modern Pharmaceutics; Third Edition; Volume 72: Cheung WK, Stravinski SS, Engel SI, Sia LL, Yacobi A, Silber BM.Pharmacokinetic evaluation of a sustained-release formulation of trihexyphenidyl in healthy volunteers.medical Research Division, American Cyanamid Company, Pearl River, NY J Pharm Sci Sep;77(9): Links.

16 P a g e International Standard Serial Number (ISSN): Garbarg S, Devissaguet JP, Prost M, Bogaievsky Y. Pharmacoclinical comparison of 2 dosage forms of trihexyphenidyl Encephale. 1983;9(2): Links. 10. Nava Dayan and Elka Touitou. Carriers for skin delivery of trihexyphenidyl HCl: ethosomes vs. liposomes.biomaterials, Volume 21, Issue 18, September 2000, Pages