Formulation and Evaluation of Prolong Release Tablet of Anti-hypertensive Drug

 

Pradip Choudhari*

HSBPVT’s College of Pharmacy, Kashti

 

ABSTRACT:

Formulation of Prolonged release dosage form has a slower absorption rate than immediate release formulation and shows minimal fluctuation in plasma levels during steady state dosing interval. Additionally, the Once-daily dosage regimen has better patient compliance. Prolonged release tablet of Anti-hypertensive drug with Eudragit RS 30 D using wet granulation method yielded optimum results and process parameters like granulation spray rate and compression machine rotor speed was found robust product development. Stability studies showed that the formulation was stable after being kept at condition of 40˚ C±2˚C/75% RH, for period of 3 months. The formulated product gave a dissolution profile similar to that of the innovator product (f2 value>80).

 

 

 

1. INTRODUCTION:

Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, convenient and safe due to its ease of administration, patient acceptance, and cost effective manufacturing process. Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption¹.

 

 

 

 

Ø Advantages of Controlled Release Drug Delivery System^[2]

·      Therapeutic advantage: Reduction in drug plasma level fluctuation, maintenance of a steady plasma level of the drug over a prolonged time period, ideally simulating an intravenous infusion of a drug.

·      Reduction in adverse side effects and improvement in tolerability: Drug plasma levels are maintained within a narrow window with no sharp peaks and with AUC of plasma concentration Vs. time curve comparable with total AUC from multiple dosing with immediate release dosage form.

·      Patient comfort and compliance: Oral drug delivery is the most common and convenient for patient and a reduction in dosing frequency enhances compliance.

·      Reduction in Health care cost: The total cost of therapy of the controlled release product could be comparable or lower than the immediate release product with reduction in side effects. The overall expense in disease management also would be reduced. This greatly reduces the possibility of side effects, as the scale of side effects increases as we approach the maximum safe concentration.

Ø Disadvantages of Controlled Release Drug Delivery System^[3]

·      Dose dumping: Dose dumping is a phenomenon whereby relatively large quantity of drug in a controlled release formulation is rapidly released, introducing potentially toxic quantity of the drug into systemic circulation. Dose dumping can lead to fatalities in case of potent drugs, which have a narrow therapeutic index.

·      Less flexibility in accurate dose adjustment: In conventional dosage forms, dose adjustments are much simpler e.g. tablet can be divided into two fractions. In case of controlled release dosage forms, this appears to be much more complicated. Controlled release property may get lost, if dosage form is fractured.

·      Poor In-vitro In-vivo correlation: In controlled release dosage form, the rate of drug release is deliberately reduced to achieve drug release possibly over a large region of gastrointestinal tract. Here the so- called ‘absorption window’ becomes important and may give rise to unsatisfactory drug absorption in-vivo despite excellent in-vitro release characteristics.

·      Increased potential for first pass clearance: Hepatic clearance is a saturable process. After oral dosing, the drug reaches the liver via portal vein. The concentration of drug reaching the liver dictates the amount metabolized. Higher the drug concentration, greater is the amount required for saturating an enzyme surface in the liver.

 

1.1 Factors Affecting Drug Release from Matrix Tablets ^[4]

·       Swelling characteristics of polymers

·       Polymer erosion

·       Drug loading

·       Drug solubility

 

2. MATERIALS AND METHOD:

Drug X was obtained as gift sample from Ipca, Mumbai. Lactose Monohydrate obtained from Meggle. Maize starch obtained from Ingredion, Colloidal silicon dioxide obtained from WackerChemle AG, Magnesium stearate from Ipca, Eudragit RS 30D from Evonik, HPMC E5 from Dow, PEG 6000 from VA-Sudha chemicals, Talc from nitika and Titanium dioxide from BimalPharma.

 

3. EXPERIMENTAL DETAILS^5-10

3.1 Complete analysis of DrugX

Drug X is official in USP,BP, IP and EP. It was manufactured and analyzed by Ipca Laboratories Ltd. as per certificate of analysis. The tests and specifications for drug substance are given in table 1.

 

 

3.2 Characterization of Innovator Product

The innovator product is the marketed product of the same of the same API and was used for comparison of data with the developed product. Characterization of the reference product was carried out for physical and chemical parameters. Physical characterization included analyzing the appearance, average weight of 10 tablets, thickness, hardness and packaging material. The innovator product was chemically analyzed for assay (percentage drug content) and related substances according the in house analytical method developed. Dissolution profile of the reference product was determined. Dissolution studies were carried out for reference product in the release medium (pH 6.8 phosphate buffer). The samples were analyzed by high performance liquid chromatography (HPLC).

 

3.3 Drug Excipient Compatibility Studies

Drug excipient compatibility studies are performed to interpret the solid state stability of the drug and excipients. Studies were conducted to investigate and predict physic chemical interaction between drug substance and excipients and thereafter to select suitable excipients compatible with the drug substance.

Study was carried out with the objective of ascertaining the compatibility of the excipients used in the formulation and to avoid in the final formulation any excipient, which is incompatible with the drug substance. Samples were analyzed both qualitatively and quantitatively for assessment of compatibility.

 

3.4 Method of Preparation of Tablet by wet granulation method

Based on literature review and nature of selected polymer (Eudragit RS30D) the development trials were started with Wet granulation by Top spray method in Fluid Bed processor.

 

Table No. 1: Formulation of Mouth Dissolving Tablet

Batch number		AEX (01/16)
Batch size		1000 tablets
S.No	Ingredients	Ph. Grade	Batch No.	Quantity (mg/tablet)
DRY MIX
1.	Drug X	Ph.Eur. 8.0	5034R	200
2.	Lactose Monohydrate	Ph.Eur. 8.0	4004	86
3.	Maize starch	Ph.Eur. 8.0	616	25
4.	Colloidal silicon dioxide	Ph.Eur. 8.0	646	2
5.	Magnesium stearate	Ph.Eur. 8.0	115	20
GRANULATION
6.	Eudragit RS 30 D	Ph.Eur. 8.0	508	50
7.	Purified water	---	---	qs
LUBRICATION
8.	Maize starch	Ph.Eur. 8.0	616	5
9.	Magnesium stearate	Ph.Eur. 8.0	115	15
COATING
10.	Hydroxy propyl methyl cellulose E5	Ph. Eur. 8.0	441	4.43
11.	Polyethylene glycol 6000	Ph. Eur. 8.0	773	1.14
12.	Talc	Ph. Eur. 8.0	49	0.57
13.	Titanium dioxide	Ph. Eur. 8.0	030	0.86
14.	Purified water	Ph. Eur. 8.0	---	qs

 

4. RESULT:

4.1 Complete analysis of DrugX

 

Table.No. 2. Test and specifications for Drug X Ph. Eur.8.0(Batch No. 5034R)

Sr.No.	Test	Specifications	Ipca Lab results (as per COA)
1.	Description	White to off white crystalline powder	White crystalline powder
Identification
2.	Specific optical Rotation	+7.0 to 10.0	+8.7
3.	Melting point	120-124 ˚C	122 ˚C
4.	pH	6.0 to 7.0	6.53
5.	Sulphated ash	Maximum 0.1%	0.05%
6.	Loss on drying (˚C)	Not more than 0.50 % w/w	0.1%
7.	Heavy metals	Not more than 10 ppm	Less than 10 ppm
8.	Assay (HPLC)	99 % to 101 %(dried substance)	99.9%
9.	Residual Solvents	Isopropyl alcohol NMT 5000 ppm	1000 ppm

 

Table.No. 3 Analysis of related substances of Drug XPh. Eur.8.0 (Batch No. 5034R)

 

Authentication of drug substance: By infrared spectrum:

 

 

Fig No. 1. Infrared spectrum of Drug X (Reference standard)

 

4.2 Characterization of Innovator Product

Table No. 4 Results for physical characterization of innovator product

 

 

Table No 5 Physical characterization results for the innovator product.

 

Chemical characterization of the Innovator product:

Table No 6 Chemical evaluation of innovator product

 

Drug release profile of Innovator product (AEX (09/16):

Table No 7 Dissolution release profile of Innovator Product

Media: 900 ml, pH 6.8 Phosphate Buffer. USP II app, RPM:75

 

Fig No. 2.Drug release profile of innovator product

 

4.3 Drug Excipient Compatibility Studies

Table No 8 Results for drug excipient compatibility studies for Drug X:

Particulars	Ratio	Impurity A		Impurity B		Unknown impurities		Total impurities
		Initial	400C/ 75%RH 1 month	Initial	400C/ 75%RH 1 month	Initial	400C/ 75%RH 1 month	Initial	400C/ 75%RH 1 month
Drug X	---	0.002	0.003	0.032	0.033	0.024	0.030	0.058	0.066
Drug X + Lactose monohydrate	1:1	0.003	0.054	0.035	0.033	0.024	0.024	0.119	0.175
Drug X + Maize starch	1:1	0.003	0.007	0.039	0.038	0.018	0.020	0.102	0.110
Drug X + Microcrystalline cellulose	1:1	0.003	0.018	0.027	0.034	0.021	0.020	0.075	0.119
Drug X + Colloidal Silicon Dioxide	1:1	0.003	0.003	0.031	0.035	0.022	0.027	0.058	0.056
Drug X + Polymethacrylate Eudragit RS 30 D)	1:0.5	0.002	0.003	0.032	0.033	0.024	0.030	0.058	0.069
Drug X + Polyethylene Glycol	1:0.5	0.006	0.005	0.028	0.049	0.024	0.042	0.281	0.252

 

4.4 Evaluation study

Table No. 9 Blend parameters of Batch number AEX (09/16)

Sr.no.	Parameters	Results
1.	Lubricated blend LOD (%)	1.26
2.	Bulk density (g/mL)	0.37
3.	Tapped density (g/mL)	0.46
4.	Compressibility index (%)	19.57
5.	Hausner’ s ratio	1.24

 

Table No. 10 Core tablet parameters of Batch number AEX (09/16)

Sr. No.	Parameters	Results
1.	Appearance	Pale yellow, capsule shape biconvex
2.	Average weight (mg)	404-406
3.	Thickness (mm)	5.67-5.71
4.	Dimensions	12.8 mm length, 6.4 mm breadth
5.	Hardness (N)	99-107
6.	Friability(%w/w)	0.212

 

Table No. 11 Coated tablet parameters of Batch number AEX (09/16)

Sr. No.	Parameters	Results
1.	Appearance	Pale yellow, capsule shape biconvex
2.	Average weight (mg)	411
3.	Thickness (mm)	5.77-5.89
4.	Dimensions	13.1 mm length, 6.7mm breadth
5.	Hardness (N)	146-157

 

 

Table No. 11 Results of Assay of Batch Number AEX (09/16)

 

Table No. 12 Drug release profile of formulation Batch AEX (09/16)with Innovator product:

Percentage drug release (No of tablets 6)
Time (min)	Innovator product	AEX (09/16)
0	0	0
1	38.9	40.5
2	51.2	53.4
3	61.5	64.6
4	68.7	71.1
6	77.3	79.8
8	87.7	87.5
10	96.1	95.3
f 2(50-100)		83

 

Fig No. 3. Comparative drug release profile of Reproducible batch AEX (09/16) along with the Innovator Product [LOT No. 078-0407]

Table No. 13 Related substances of Batch AEX (09/16)

Related substances (%)	Innovator product	AEX (09/16)
Impurity A	0.032	0.015
Impurity B	0.023	0.024
Unknown Impurities	0.052	0.042
Total impurities	0.107	0.081

 

4.5. Evaluation of stability batch:

Table No. 14 Evaluation of stability data of batch AEX (09/16)

Pack: Alu/PVC blister.

TESTS		RESULTS
Stability Time and condition		( 3 Months, 25ºC/60%RH)	( 3 Months, 40ºC/75%RH)
Appearance		Pale yellow, biconvex, capsule shaped tablets.	Pale yellow, biconvex, capsule shaped tablets.
Average weight		412-414 mg	412-413 mg
Hardness		146-154N	148-152 N
Thickness		5.79-5.89 mm	5.78-5.86 mm
Assay		99.23 %	98.53 %
Dissolution		51.4 %  at 2 Hrs 70.5 % at 6 Hrs 96.7 %  at 10 Hrs.	53.6 %  at 2 Hrs 71.8 % at 6 Hrs 95.3 %  at 10 Hrs.
Impurities	Impurity A	0.029%	0.054 %
	Impurity B	0.029%	0.027 %
	Unknown Impurities	0.046%	0.075 %
	Total impurities	0.096	0.110%

 

5. DISCUSSIONS:

In the present study the objective of this project work was to develop and evaluate a prolonged release tablet of drug X. All requirements as per EP monograph of drug product were fulfilled. The formulated product was found to be and stable (40˚C/75% RH for 3 months). The formulated product gave a dissolution profile similar to that of the innovator product (f2 value>80). Thus, the objectives envisaged in this thesis were fulfilled.

 

6. REFERENCES:

1.     Ali Nokhodchi, Saishta Raja, The role of oral controlled release matrix tablets in drug delivery system; Bioimpacts; 2012; v2(4); 175-187.

2.     Nellore RV, Development of extended release matrix tablet formulation for regulatory policy consideration, controlled release, 1998, Jan 2, 50(1-3),247-56.

3.     Honey priyajames, smart polymers for controlled delivery of drugs, Acta Pharmaceutics Sinica B, April 2014, V-4,I-2, pg (120-27).

4.     ICH guidelines, Q1A (R2): Stability Testing of New Drug Substances and Products (Revision 2), International Conference on Harmonization.

5.     ICH Harmonised Tripartite Guideline stability testing: Photo stability testing of new drug substances and products Q1B. 

6.     Harnish Patel et al, Matrix Type Drug Delivery System: A Review, Journal of Pharmaceutical Sciences and Bioscientific Research, 2011, 1(3), 143-151.

7.     Shalaka Dhat et al, Effect of Two Different Diluents On Release Profile Of Aceclofenac From Sustained Release Matrix Tablets Using Gum Damar As Release Retardant, International Journal of Pharmacy and Pharmaceutical Sciences, 2011, 3(4), 307-313.

8.     Borguist P, Korner A, Larsson A: A model for the drug release from a polymeric matrix tablets-effect of swelling and dissolution. Journal of Controlled Release, 2006, 113, 216-225.

9.     John C and Morten C. The Science of Dosage Form Design, Aulton: Modified release peroral dosage forms, 2nd edition, London, Churchill Livingstone; 2002, p. 290-300.

10.   Basak SC, Reddy JBM, and Lucas Mani KP, Formulation and release behaviour of sustained release ambroxol hydrochloride HPMC matrix tablet, Indian Journal of Pharmaceutical Sciences, 2006, 5(68), 594- 598.

 

 

 

 

 

Received on 16.02.2018       Modified on 16.04.2018

Accepted on 06.06.2018       ©A&V Publications All right reserved