Concurrent Process Validation of Ramipril Tablets

S. Karthik, Ashok Kumar P.*, Suresh V. Kulkarni, Someshwara Rao and Babitha S.

Dept. of Pharmaceutics, Sree Siddaganga College of Pharmacy, BH Road, Tumkur-572102, Karnataka, India.

*Corresponding Author E-mail: ashokkumarscp@yahoo.com

ABSTRACT:

The prime objective of any pharmaceutical plant is to manufacture products of requisite quality at the lowest possible cost. Good manufacturing practices for pharmaceutical products require that critical processes, which may affect product quality, have to be validated. The rationale behind this is that if more effort is placed on development and validation at the beginning, then there will be no chance for failure during product life. The main objectives of process validation are to prove that the process is consistently undergoing what it is supposed to undergo which means that the process is under control and to determine the process variables and acceptable limits for these variables and to set up appropriate in-process controls. The application of a process validation program simply proves that the process step being evaluated reliably does what was expected of it. A successful process validation effort thus builds quality into the process so that the reliance on end product testing can be minimized. In the present study, concurrent process validation studies were carried out for Ramipril as per the Batch production record. The tablets were evaluated for various physiochemical parameters by official procedures. The invitro dissolution studies were carried out in 0.1 M HCl and the results were found to be 97%, 95% and 96% respectively for the three batches at the end of 45 minutes. The results for the assay were found to be within the acceptance criteria. From the validation studies carried out, it was observed that no modifications are required in the present manufacturing process. The method requires further validation only when there is change in raw materials or equipment or process.

KEYWORDS: Validation, Concurrent process validation, Good manufacturing practices, Ramipril tablets.

INTRODUCTION:

The prime objective of any pharmaceutical plant is to manufacture products of requisite attribute and quality consistently at the lowest possible cost. Although validation studies have been conducted in the pharmaceutical industry for a long time, there is an ever increasing interest in validation owing to the industry’s greater emphasis in recent years on quality assurance and productivity improvement. Validation is a necessary part of a quality assurance program and is fundamental to an efficient production operation.¹ Validation is a concept that has evolved in the United States of America in 1978. The concept of validation has expanded through the years to embrace a wide range of activities from analytical methods used for the quality control of drug substances and drug products to computerized systems for clinical trials, labeling or process control. Validation is founded on, but not prescribed by regulatory requirements and is best viewed as an important and integral part of current Good Manufacturing Practices.

The word validation simply means assessment of validity or action of proving effectiveness.² According to the Food and Drug Administration (US FDA) validation is defined as “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes”.³Concurrent validation is established documented evidence that a process does what it purports to do based on the information generated during actual implementation of the process. This is performed on two instances i.e. for an existing system or a process and for verification of proper installation along with specific operational tests done in case of an existing infrequently made product. ⁴A validated process is a systematic, documented program that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. The documentation, including protocols, data, and results obtained from process validation and equipment qualification are important, since the validation performed should be auditable by an appropriate responsible individual who, after reviewing the records, should be able to certify the validation of the process to produce products to defined attributes consistently provided that the system validated is not altered.⁵Good manufacturing practices, well defined specifications, sound sampling procedures, and efficient process controls do not in themselves constitute an overall quality control program. Unless the testing procedures by which the product quality is finally measured are established on an equally sound basis, the entire system may be deficient.⁶The conceptual framework of good validation practices are:-

1. Technology should meet business needs.

2. Technology should continue to meet business needs.

3. Technology should be developed in a quality manner.

4. Technology should be implemented effectively in our environment.

5. Documentation should be complete and current.

6. Only qualified staffs to develop maintain and use technology.

7. Appropriate level of independent quality control.⁷

Ramipril is an anti-hypertensive drug used to treat all forms of high blood pressure. Ramipril is a potent and orally active inhibitor of angiotensin converting enzyme (ACE). It is a prodrug, which is hydrolyzed in the liver after absorption from the gastrointestinal tract to form the active ACE inhibitor, ramiprilat. This prodrug itself is a poor inhibitor of ACE, but its active metabolite has a higher affinity for ACE, thus blocking the conversion of the angiotensin I to angiotensin II, a highly potent vasoconstrictor and thereby leading to a reduction in vasopressor activity and a decrease in peripheral vascular resistance.⁸

MATERIALS AND METHODS:

Ramipril was obtained courtesy of AstraZeneca Pharma India Limited, Bangalore. The excipients used were Hydroxy propyl methyl cellulose (HPMC), Lactose anhydrous, Ferric oxide yellow, Sodium starch glycollate and Sodium stearyl fumarate and were from AstraZeneca Pharma India Limited, Bangalore. All materials used were of pharmaceutical grade.

Preparation of Ramipril tablets:

Ramipril tablets were prepared by dry granulation as per the formula given in Table 1. Ramipril and a little quantity of HPMC were mixed in a polybag for 5 minutes and sifted through 30 mesh sieve in a vibratory sifter and charged into a double cone blender (100 litres). The remaining quantity of HPMC and lactose anhydrous were sifted through 30 mesh sieve, transferred to a double cone blender and mixed for 30 minutes. The entire blend was unloaded and sifted through 40 mesh and reloaded into double cone blender (100 litres). Sodium starch glycollate was sifted through 100 mesh and premixed with Ferric oxide yellow and the blend was passed through 100 mesh in a vibratory sifter and charged into a double cone blender (25 litres) and mixed for 15 minutes. Lactose anhydrous was sifted through 40 mesh sieve and charged into double cone blender for 45 minutes. The complete blend was passed through 40 mesh four times and again charged into double cone blender for 5 minutes. Sodium stearyl fumarate was sifted through 60 mesh sieve and added to the double cone blender and mixed for 5 minutes. The granules were collected into a labelled double polybag lined High density polyethylene (HDPE) containers. Tablets were compressed at 100 mg weight on a 27 station rotary tableting machine (Cadmach Pvt Ltd, Ahmedabad) with 8 X 4 mm capsule shaped punches.

Table-1 Tablet composition of Ramipril tablets (Batch size is 4 lakhs)

Ingredients	Uses	Quantity (Kg)
Ramipril	Drug	1
HPMC	Binder	8
Lactose anhydrous Ferric oxide yellow Sodium starch glycollate Sodium stearyl fumarate	Diluent Colour Disintegrant Lubricant	12g 0.04 4.80 0.80

Evaluation of granules:

The angle of repose was measured by using funnel method⁹, which indicates the flowability of the granules. Loose bulk density (LBD) and tapped bulk density (TBD) were measured using the formula: LBD= weight of the powder / volume of the packing. TBD= weight of the powder / tapped volume of the packing. Compressibility index¹⁰ of the granules was determined by using the formula: CI (%) = [(TBD-LBD/TBD)] ×100.The physical properties of granules were shown in Table 2.

Evaluation of tablets:

All tablets were evaluated for its drug content, hardness, friability and thickness according to official methodsshown in Table 3.

Drug content:

The drug content was determined by liquid chromatography. One tablet was taken and added to 5 ml of 0.1 M HCl and sonicated for 10 minutes and diluted if necessary with 0.1 M HCl to produce a solution. Centrifuge and use the supernatant which contains 0.00025% w/w of Ramipril.

Dissolution studies:

Invitro dissolution studies were carried out using USP XXII dissolution apparatus type I (Electrolab, India) at 75 rpm for 45 minutes. The dissolution medium consisted of 900 ml of 0.1 M hydrochloric acid, maintained at 37+ 0.5⁰ C. The study was performed in triplicate. Not less than 70% of the stated amount of Ramipril C₂₃H₃₂N₂O₅.

Assay:

The assay was carried out by liquid chromatography Test solution was prepared weighing a quantity of powdered tablets (20 tablets) containing 25 mg Ramipril and then it was dispersed in 100 ml of 0.1 M HCl and centrifuged. 1 ml of the resulting solution was diluted to 100 ml with 0.1 M HCl. The reference solution was 0.00025% w/v solution of Ramipril standard in 0.1 M HCl. The Ramipril tablets contain not less than 90.0% and not more than 110.0% of the stated amount of Ramipril, C₂₃H₃₂N₂O₅.

RESULTS AND DISCUSSION:

Granules prepared for compression of tablets were evaluated for various parameters shown in Table 2. The results of angle of repose (< 30) was in the range of (26.12 º± 1.25 to 31.15º± 1.55) which indicates good flow properties of the granules ^11,12. The bulk density of the granules formulation was in the range of (0.301± 0.004 to 0.314± 0.006); the tapped density was in the range of (0.282± 0.010 to 0.317± 0.014), which indicates that the powder was not bulky. This was further supported by lower compressibility index values in the range of (8.94± 0.65 % to 9.87± 0.74 %), indicating compressibility of the tablet blend is good. These values indicate that the prepared granules exhibited excellent flow properties.

Table-3 Evaluation of post compression parameters for various batches of Ramipril

Batch Number	Hardness (kg/cm²)	Friability (%)	Drug content	Thickness (mm)
B1	4.5± 0.10	0.12 ± 0.2	97 mg	2.97
B2	4.5± 0.10	0.12 ± 0.2	99 mg	2.98
B3	4.5± 0.10	0.12 ± 0.2	100 mg	3.01

The values represent mean ± S.D; n= 6

Figure 1. Invitro dissolution profile of batches B1, B2 and B3.

The Ramipril tablets were a pale yellow coloured capsule shaped tablet with scoreline on one side. The results of post compression parameters are shown in Table-3. The thickness of tablets were measured by vernier caliper and ranged between (2.97 ± 0.04 and 3.03 ± 0.01). The hardness of the tablets was measured by Monsanto tester and was found to be 4.5 kg/cm²for all the three batches. Tablet hardness is, however, not an absolute indicator of strength. The percentage friability of the tablets of the three batches were all found to be 0.12% , which was below 1% , indicating that the friability is within the prescribed limits and also an indication of good mechanical resistance. The drug content for batches B1, B2 and B3 was found to be 97, 99 and 100 mg respectively which comply with official specifications. The results of the dissolution studies for batches B1, B2 and B3 are shown in Figure 1. The percentage dissolution for batches B1, B2 and B3 was found to be (97%, 95% and 96%) at the end of 45 minutes respectively. The results of the assay for the three batches B1, B2 and B3 are shown in Table 4.

Table-4 Assay values from three batches of Ramipril tablets

Batch Number	Assay (%)
B1	98
B2	97
B3	97

The values represent mean ± S.D; n= 6

CONCLUSION:

The concurrent process validation studies were carried out for three batches of Ramipril tablets. From the above observations it was concluded that no modifications are required in the present manufacturing process. The formula used for the manufacture of Ramipril tablets was robust and the process is under control. The specifications and results complies with the official pharmacopoeia. The method requires further validation only when there is a change in the raw materials or equipment or process.

ACKNOWLEDGEMENT:

The authors are thankful to AstraZeneca Pharma India Limited and the management of Sree Siddaganga College of Pharmacy for providing the necessary facilities to carry out this work.

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Received on 05.05.2011 Modified on 18.05.2011

Research J. Pharm. and Tech. 4(8): August 2011; Page 1281-1283

Batch Number	Angle of repose	Loose bulk density (LBD) (g/cc)	Tapped bulk density (TBD) (g/cc)	Compressibility index (%)
B1	26.12°±1.25	0.314± 0.006	0.282± 0.010	8.94± 0.65
B2	31.15°±1.55	0.301± 0.004	0.317± 0.014	9.87±0.74
B3	27.23°± 1.36	0.313±0.005	0.312± 0.012	9.32±0.71