Formulation and Process Scale up of Misoprostol Tablets

 

N. Sravanthi*, K. Alekhya and S. Punitha

Prist University, Thanjavur, Tamil Nadu

*Corresponding Author E-mail: nalla.sravanti@gmail.com

ABSTRACT:

In the present work, Process scale – up will minimize the havoc that arises during manufacturing process of new products, which has potential threat of manufacturing variables that affect the quality of final product. It gives a deep understanding of the process involved in the manufacturing and thus enables one to have better process knowledge. Needless to say, the importance of scale – up was realized by the leading regulatory authorities like USFDA, by releasing the limits for the processes involved, change in equipment and how it has to be demonstrated to show that the product developed and marketed are same.

 

 

 

INTRODUCTION:

Process scale – up is generally defined as the process of increasing the batch size. Successfully scaling-up a pharmaceutical dosage form should be treated as the final step in product development¹. A thorough understanding of the formulation and process variables is essential for the progression of new products from pilot to commercial batch sizes. In moving from RandD to production scale, it is sometimes essential to have an intermediate batch scale. Misoprostol is a prostaglandin analogue, indicated for reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)-induced gastric ulcers in patients at high risk of complications from gastric ulcer². Cytotec is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer³.

 

FORMULATION DEVELOPMENT

The US product (Cytotec) contains Hypromellose, Microcrystalline cellulose, Sodium starch glycolate and Hydrogenated castor oil as excipients in their formulation. Since the molecule is relatively new and sensitive to moisture, it was decided to go with the same excipients used in Cytotec⁴. The quantities of excipients used are well within the limits given in inactive ingredient guide of USFDA⁵.

 

Method of Preparation: Misoprostol, Micro crystalline cellulose and castor wax were triturated in a glass mortar, finally sodium starch glycolate was incorporated in the powder mixture followed by direct compression⁶.

 

Trial batches compilation:

B.No:	KOA01	KOA02	KOA03
INGREDIENTS (in mg/tablet)
Misoprostol (1% HPMC dispersion)	20.0	20.0	20.0
Microcrystalline cellulose	173.8 (PH101 grade)	173.8 (Avicel PH102)	166.0 (Avicel PH112)
Sodium starch glycollate	8.2	8.2	12.0
Castor wax	2.0	2.0	2.0
IPQC Parameters
Avg. Wt (mg)	201.0	208.0	204.0
Hardness (kg/cm2)	5-6	5-6	5-6
Friability (%w/w)	0.02	0.02	0.02
Disintegration time (min)	~2	10 seconds	15 seconds
Thickness (mm)	3.29	3.71	3.70
Dissolution (%w/w)	-	103.12	105.27

 

 

Since the literature cites that the misoprostol degradation increases with increase in of the API, Microcrystalline cellulose with low moisture is finalized. Based on the satisfactory product characteristics KOA03 is finalized. The tablets are uncoated^{4, 7, 8}.

 

Development of packing material⁹

Marketed product is packed in Alu/Alu blister. Based on the availability of machinery and preliminary stability studies, Alu/Alu strip pack is finalized.

 

 

RESULTS:

COMPARATIVE DISSOLUTION STUDY RESULT¹⁰

Table 1a: Comparative Dissolution Data

S.N0.	Misoprostol Tablets  B.No: KAO 03			CYTOTEC (PHARMACIA)
	15 min	30 min	45 min	15 min	30 min	45 min
1	65.47	78.29	93.08	66.22	84.10	95.55
2	66.12	77.46	94.67	65.87	87.94	94.37
3	67.28	78.54	95.12	65.21	80.34	96.39
4	64.39	79.21	92.39	64.97	83.67	96.18
5	63.57	75.88	93.65	66.87	82.19	94.47
6	68.24	77.91	94.28	65.59	86.49	94.03
7	65.39	76.66	96.21	68.31	82.21	96.12
8	66.39	79.68	94.21	64.27	83.68	95.84
9	64.57	75.36	91.08	65.08	84.96	93.67
10	66.89	78.91	93.22	68.37	85.51	95.78
11	64.02	79.68	95.41	64.57	83.29	94.29
12	63.79	78.67	90.88	69.34	85.47	97.21
Average	65.51	78.02	93.68	66.22	84.15	95.33
f2=73

 

Table 1b: Comparative Data for Graphical Representation

Product	Time in minutes
	0	15	30	45
Misoprostol Tablets 200 mcg	0	65.51	78.02	93.68
Cytotec (Pharmacia)	0	66.22	84.12	95.33

 

 

Chart 1   :  Chart showing the comparison between average releases of tablets for both the brands.

 

 

INITIAL AND STABILITY ANALYSIS^{11, 12}

Table 2: ANALYTICAL RESULTS COMPILATION OF FINALIZED FORMULA.

Parameters	Specification	Initial	40°C/75%RH			30°C/65%RH
			1M	2M	3M	3M
Description	White, rectangular, slightly biconvex,     uncoated tablets with two squares    debossed with a break line on one side.	C	C	C	C	C
Disintegration time	NMT 15 min	2 – 3 min	2 – 3 min	2 – 3 min	2 – 3 min	2 – 3 min
Dissolution	Not less than 70% of the labeled amount of Misoprostol dissolved in 45 min	95.5	93.8	93.1	92.0	95.2
Assay	90 – 110% w/w	99.8	99.5	99.2	98.6	99.8

C = White, rectangular, slightly biconvex, uncoated tablets with two squares debossed with a

Break line on one side

 

PROCESS SCALE – UP RESULTS:

Results of final blending:

Table 3: Uniformity of content during final blending

Sample No	Misoprostol
	B. No: C-1	B. No: C-2	B. No: C-3
1	98.06	98.63	101.04
2	97.41	101.05	99.60
3	93.85	94.68	93.75
4	103.17	100.40	98.31
5	95.85	97.13	100.20
6	97.05	96.85	98.12
7	97.20	93.70	96.45
8	102.50	97.50	100.64
9	93.79	94.26	95.82
10	96.84	93.04	95.20
MEAN	97.57	96.72	97.91
RSD	3.20	2.88	2.56

Assay % w/w

RSD ≤ 5.0 % and all individuals are within ± 10 % of mean absolute.

 

Results of uniformity of content (compression stage)⁶

Table 4a: Uniformity of content: B. No: C-1

Sample No	Initial	Middle	End
1	94.20	102.40	101.40
2	97.98	98.30	98.70
3	95.30	101.90	98.25
4	93.60	101.80	97.67
5	96.13	103.20	101.40
6	100.94	102.60	94.72
7	101.53	100.70	94.50
8	97.10	99.80	103.70
9	95.89	102.90	103.53
10	99.00	101.70	104.69
MEAN	97.17	101.53	99.86
RSD	2.62	1.42	3.47

Assay % w/w

RSD ≤ 6.0 % and all individuals are within ± 10 % of mean absolute.

 

Table 4b: Uniformity of content: B. No: C-2

Sample No	Initial	Middle	End
1	95.93	102.90	102.00
2	102.00	102.12	103.10
3	100.19	99.06	95.20
4	100.37	100.29	100.30
5	96.47	101.20	96.00
6	96.71	99.77	95.30
7	101.16	98.25	97.20
8	102.79	102.82	103.00
9	103.20	98.09	92.00
10	102.20	102.31	102.20
MEAN	100.10	100.68	98.63
RSD	2.61	1.74	3.82

Assay % w/w

RSD ≤ 6.0 % and all individuals are within ± 10 % of mean absolute.

DISCUSSION:

The manufacturing of Misoprostol tablet is carried out as per the approved manufacturing procedure. The manufacturing process flow is as given below.

 

Table 4c: Uniformity of content: B. No: C-3

Assay % w/w RSD ≤ 6.0 % and all individuals are within ± 10 % of mean absolute.
Sample No	Initial	Middle	End
1	101.50	103.40	100.49
2	103.20	98.17	96.85
3	102.42	101.96	101.22
4	99.12	102.63	98.64
5	98.46	99.82	100.37
6	99.75	104.29	101.40
7	95.98	100.58	101.65
8	96.49	99.54	99.70
9	102.11	95.60	102.04
10	101.95	102.93	100.21
MEAN	100.10	100.89	100.26
RSD	2.41	2.52	1.48

 

RESULTS OF LEAK TESTING (PACKING STAGE)⁹

Table 5: Leak test of finished products

TIME POINTS	B. No.
	Limits	B. No: C-1	B. No: C-2	B. No: C-3
1	No Leak	No Leak	No Leak	No Leak
2	No Leak	No Leak	No Leak	No Leak
3	No Leak	No Leak	No Leak	No Leak

 

CONCLUSION:

Literature was collected for tablet dosage forms, Misoprostol, excipients used and comparative dissolution profiling. Formulation developed is analyzed and found to comply the established specification. Comparative dissolution profile was performed and found to be similar to the innovator product. The finalized formula passes stability studies and based on this process scale – up was performed with the batch size of 2.0 lakh tablets. All the process scale– up parameters are found to comply with the established specification. The data obtained from this research work reveals that the formula developed is similar to the innovator product characteristics with respect to quality and is successfully scaled up.

 

REFERENCES:

1.        Lachman Leon, Lieberman H.A. and Kanig J.L., “The theory and practice of Industrial Pharmacy” (3^rd edition), Varghese Publishing house Bombay.

2.        Lippincott Williams’s et.al. “Oral Solid Dosage Form: Remington- The Science and Practice of Pharmacy” 20^th edition, Vol-1, 2001, 859-871.

3.        CYTOTEC prescription information from PDR (Physician Desk Reference).

4.        Pharm Res. 1990 Nov;7(11):1186-9. Kararli TT, Catalano T, Stabilization of misoprostol with hydroxypropyl methylcellulose (HPMC) against degradation by water.

5.        “Handbook of pharmaceutical Excipients” Edited by: Raymond C Rowe, Paul J Sheskey and Siân C Owen.

6.        Lieberman H.A. et.al. “Compression- Pharmaceutical dosage Form, Tablets” Marcel Decker Inc New York, Vol-2, 1990, 153-182.

7.        Banker G.S., “Tablets: theory and practice of Industrial Pharmacy”, 3^rd, Varghese Publishing house.

8.        Loyd V.A, Nicholas G.P and Howard C.A “Ansel’s Pharmaceutical Dosage form and Drug Delivery System”, Chapter 8, 3^rd edition.

9.        Jennifer G. Allinson et.al “The effect of Packaging on the stability of a moisture sensitive compound” Int. Journal of P’ceutics, Vol-221, 2001pg- 49.

10.     Dissolution Profile Comparison Using Similarity Factor, f2; Vinod P. Shah, Yi Tsong, Pradeep Sathe and Roger L. Williams; Office of Pharmaceutical Science, Center for Drug Evaluation and ResearchFood and Drug Administration, Rockville, MD.

11.     ICH Guidelines Q1A (R2) “Guidance for Industry, Stability testing of new drug substances and products” (http://www.ich.org).

12.     “British Pharmacopoeia” 2002 Volume-2:2297.

 

 

 

Received on 15.04.2010          Modified on 20.09.2010

Accepted on 29.09.2011         © RJPT All right reserved