Polymorphism: A Dissolution Rate Enhancement Technique of Nitrendipine

N Jawahar*, R Sureshkumar, D Nagasamy Venkatesh, GNK Ganesh, S Jubie,  MK Samanta and B Suresh

 

Department of Pharmaceutics, J.S.S College of Pharmacy Rockland, ooty-643001 Tamil Nadu India

* Corresponding Author E-mail: jajupharma@yahoo.co.in

 

ABSTRACT

Nitrendipine an anti hypertensive drug which is practically insoluble in water. But water insolubility and the less bioavailability are the limitations of its effective use clinically. The present investigation aims to study the effect of various solvent on the modifications of Nitrendipine. The different forms of crystals were prepared by using  various solvents such as acetone, benzene, methanol and blends of   methanol with polyvinyl pyrrollidone (PVP- K30) and polyethylene glycol(PEG-4000).The prepared crystals were characterized  by different physico-chemical techniques such as melting point, solubility, spectroscopic analysis and dissolution .The results indicate that the crystals obtained from different solvents exhibited different physiochemical characters. In conclusion ,the crystals prepared from benzene, PVP- K30 and PEG-4000 shows higher dissolution rate would result in an improved bio-availability

 

KEY WORDS              Nitrendipine, polymorphism, crystals, bio-availability

 

INTRODUCTION:

Nitrendipine is a dihydropyridine calcium channel blocker used in the treatment of hypertension1. Nitrendipine is insoluble in water and other aqueous fluids. As such its oral absorption is dissolution rate limited. The poor aqueous solubility of the drug gives rise to difficulties in the formulation of solid dosage forms and leads to poor variable dissolution rate and bioavailability. Among the various methods to overcome these problems, polymorphism2,3 is an industrially accepted technique. Because many crystalline  modifications  may  have  sufficient difference in their physical and thermodynamic properties so that stability and bioavailability may be improved. The present work is to study the effect of various solvents such as acetone, benzene, methanol and blends of methanol with poly vinyl pyrrolidone (PVP K30) and poly ethylene glycol (PEG-4000) on the crystal forms of nitrendipine. The crystalline materials were characterized by melting point, solubility, spectroscopic analysis, and dissolution studies.

 

MATERIALS AND METHODS:

Materials

Nitrendipine  was  obtained  as  generous  gift  from Corrette (USA) Chemical works. The solvents used for the present work were acetone, benzene and methanol obtained from  Ranbaxy Chemical  Lab  (SAS  Nagar, India.).   Tween 80, PVP K30, PEG-4000 used was of the pharmacopoeial grade.

 

Methods

Preparation of Nitrendipine crystals

Nitrendipine   crystals   were   prepared   by   two   different methods such as salvation methodusing different solvents like acetone, benzene, methanol and solvent change method5 using methanol blends of PVP and PEG.

 

Method I:

Nitrendipine 1  gm was dissolved separately in  50  ml  of selected  solvent  was  heated  at  the  boiling  point  of  the respective solvent. Then the solution was filtered and concentrated by left at room temperature until the solvent was completely evaporated to form the crystals. Then the crystals were further dried under vacuum and stored in a desiccator.

 

Method II:

Nitrendipine 1 gm was dissolved in 40 ml of methanol was heated, filtered and concentrated on a water bath at 78º  C. The resultant clear solution was added to equal volume of cold water (5ºC) containing 2%W/V solution of Tween 80, PVP-k30 and PEG-4000 separately under agitation and then left for 1 h at room temperature. The crystals were recovered by filtration under vacuum and stored in desiccators for further use.

 

Characterization of crystals

The prepared crystals were characterized for melting point, FT- IR, solubility and dissolution studies by official reported methods.

a)    Melting  point  determination6   Melting  point  of  the parent  drug  and  its  newly  developed crystal  forms  were determined  by  using electrically heated  capillary  melting point apparatus.

b) Spectroscopic analysis7 The structure behaviors of parent drug and the newly developed crystal forms of nitrendipine were   determined   by   using   FT-IR   spectroscopic analysis. (PERKIN ELMER USA MODEL)

 

c) Solubility studies: The solubility of parent drug and the newly developed crystal forms of nitrendipine in water were studied by method used in USP. In this method nitrendipine 50 mg was weighed and shaken with 25 ml of water in a mechanical shaker (100 rpm) at 37 ± 0.5°C for 24 h. It was filtered and 1 ml of the filtrate was pipette out and diluted to 100 ml water. The absorbance was  measured at 235 nm.

 

d) Dissolution studies8: All dissolution studies were performed by using USP XXI paddle apparatus (Type- I) 20 mg of nitrendipine and its crystals filled in a capsule was transferred to a the dissolution media (900ml of phosphate buffer pH-6.8) at 37±0.50OC and stirred  at  100rpm  .The  drug  concentration  in  the solution was determined at selected time interval by measuring the absorbance at 235nm a Shimadzu 1600

–UV-Visible spectrometer.

 

 

FIGURE1:  in-vitro  drug  release  profile  of  nitrendipine and its new crystal

 

RESULTS AND DISCUSSION:

The crystals obtained from various solvents subjected to melting point determination were found that the melting points of the new crystals were considerably varying with parent drug. Crystals prepared with PVP- K30  as a solvent showed a comparatively less reading which is an indication of high solubility.

 

In  the  solubility  studies,  the  drug  crystals  obtained from PEG-4000 and PVP -K30 showed higher solubility than other crystals. The crystals obtained from other solvents such as benzene, methanol and TWEEN 80 showed slight inverse insolubility than the pure drug.

 

The dissolution profile revealed that the rate of dissolution increased in crystal from different solvents than  nitrendipine.  Crystals  obtained  from  benzene, PVP-K30 and PEG-4000 showed higher dissolution rate than nitrendipine because of the better crystallinity of the modified crystals. A highest rate of dissolution was obtained from PVP-K30 crystals.

 

TABLE.1 Solubility and Melting point data of nitrendipine and its new crystal forms from various solvents

S.No

Drug/Solvent

system used

Melting  point

(0C)

Solubility

(mg/ml)

1

Nitrendipine

148

1.957

2

Benzene

128

2.889

3

Acetone

145

2.225

4

Methanol

140

2.491

5

PVP

124

3.421

6

PEG

130

3.288

7

Tweeen 80

138

2.624

 

The FTIR spectra of all modified crystals stored at ambient condition were identical and the main absorption band of nitrendipine appeared in all of the spectra. This indicates that there was no difference between the internal structure and confirmations of these samples, because these were not associated with the changes at molecular level.

 

From the results it is evident that the crystals obtained from different solvents exhibit different physicochemical properties. The physico-chemical properties of the solvent might have played a role in conferring different characteristics to the crystals of nitrendipine. Different crystalline modification of nitrendipine facilitating improved dissolution rate  and  solubility. It  may  be  concluded that different crystalline modification by selecting a suitable solvents significantly improved dissolution rate would result in an improved bioavailability because dissolution rate is the rate controlling step in drug absorption following oral administration.

 

REFERENCES:

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4.     Shivakumar.HG and Ramalingaraja G. Influence of solvents on the crystal habit and properties of paracetamol. Ind. J. Pharm. Sci.1999; 61(2).

5.     Albert HL Chow, John D Gorden. Modification of phenytoin crystals. Int. J. Pharm. 1995; 126:11-19.

6.     Mbang N, Femi-Oyewo, Spring MS. Studies on paracetamol crystals produced by growth in  aqueous solutions. Int. J. Pharm. 1994; 112:17-28.

7.     Adhiyaman R and Basu SK. Crystal modification of dipyridamole using different solvents and crystallization conditions. Int. J. Pharm. 2006; 321: 27-34.

8.     Dilip  Kaul,  Nguyen  T,  Nguyen  Suresh  Vanketram.Crystal   habit   modifications   and   altered   tableting characteristics. Int. J. Pharm. 1992; 88: 345-350.

 

Received on 24.07.2008    Modified on 22.08.2008

Accepted on 30.08.200 © RJPT All right reserved

Research J. Pharm. and Tech. 1(3): July-Sept. 2008; Page 285-286