EFFECT OF CERTAIN POLYMERS ON THE RELEASE CHARACTERISTICS OF NIMODIPINE

EFFECT OF CERTAIN POLYMERS ON THE RELEASE

CHARACTERISTICS OF NIMODIPINE

Esmat E. Zein El Dien1, Nageh A. El Mahdy2 and Wesam Samy3*

1

Professor of Pharmaceutical Technology, Pharmaceutical Technology Dept., Faculty of

Pharmacy, Tanta University, Egypt.

2

Professor of Pharmacology, Pharmacology Dept., Faculty of Pharmacy, Tanta University,

Egypt.

3

Pharmacist at General Mahalla Hospital, El-Mahalla El-Koubra, Egypt.

ABSTRACT

Nimodipine(NMD) is used in the treatment of various cardiovascular

disorders such as angina pectoris, cardiac arrhythmia and hypertension.

The major problem of this drug is its very low solubility in biological

fluids as well as poor bioavailability after oral administration. An

attempt has been made for enhancement of nimodipine dissolution rate

by utilizing solid dispersion technique, the effect of different polymers

on the physicochemical characterstics of the drug was studied, FTIR

and DSC Studies proved that no chemical interaction between drug and

excipients. The formulations prepared with solid dispersion using

(PVP 40, Gelucire 44/14 HPMC E5 and Gelucire44/14) showed complete drug release

between 3 - 9 min. However the formulations prepared with HPMC E5 only, PVP 40 and

Gelucire 44/14 alone solid dispersions did not give drug release in specified time. Among all

formulations NMD prepared with (PVP 40 and Gelucire 44/14) as polymers showed 95%

drug release within 10 minutes. From the results it would be concluded that, nimodipine SD

showing enhanced dissolution will lead to, improved effectiveness and hence better patient

compliance.

KEYWORDS: Nimodipine, PVP 40, Gelucire44/14, HPMCE5, Solid dispersion.

INTRODUCTION

Poor aqueous solubility of drugs is a major limiting factor with many new drugs in their

successful launch in market in spite of their potential pharmacokinetic activity. Poor

7105 – 2277 ISSN Research Article . 183 -171 Volume 5, Issue 7,

*Corresponding Author Wesam Samy

Pharmacist at General

Mahalla Hospital, El-Mahalla

El-Koubra, Egypt. Article Received on 10 May 2016,

Revised on 30 May 2016, Accepted on 20 June 2016

solubility (less than 10%) of a drug, leads to poor dissolution in the gastrointestinal tract

(GIT) hence, incomplete and erratic absorption ultimately limits its clinical utility.

Further, poorly soluble drugs are generally administered at much higher doses than the actual

dose in order to achieve necessary drug plasma levels leading to increased adverse reaction &

cost of therapy and often yields erratic pharmacological response and hence poor patient

compliance.

About 40% of drugs being in the pipeline of pharmaceutical companies are poorly soluble,

which emphasizes the need of a technique to overcome such problems. Poorly water-soluble

drugs are associated with slow drug dissolution followed by slow absorption leading

eventually to inadequate and variable bioavailability. Solubilty, as the dissolution rate is the

most essential factor controlling the rate and extent of drug absorption, a poorly water soluble

compound is defined which gets soluble less than 1part per 10000 part of water.[1]

A poorly water soluble drug, more recently, has been defined in general terms which

requires more time to dissolve in the gastrointestinal fluid than it take to be absorbed in the

gastrointestinal tract.

A greater understanding of dissolution and absorption behaviors of drugs with low aqueous

solubility is required to be successfully formulated into bioavailable drug products.[2]

Nimodipine (NMD), a Calcium channel blocker, was selected as a model drug for this work

as the drug has low aqueous solubility where its GIT absorption is limited by its dissolution

in the gastrointestinal fluids exhibiting a low bioavailability after oral administration.[3] a

number of approaches are practiced to improve theaqueous solubility of poorly soluble drugs

viz., soliddispersion (solvent evaporation method), sphericalagglomeration[4],

microcrystallization[5] and supersaturation.[6] These techniques result into polymorphic

changes or changes in crystal structure or hydrophilicity changes due to formation of a

molecular dispersion. the formulations were evaluated by studying these changes in drugs

along with their dissolution and other properties.[7] the solubility and in vitro study were

evaluated spectrophotometerically in the dissolution media. The polymorphic forms of the

drug was evaluated by the differential scanning calorimetry (DSC) & the crystal structure

determination were done by the powder X-ray diffraction studies (XRD) at the different

angles. In the present work solid dispersion technique of nimodipine with certain polymers

pyrrolidine 40(PVP 40), Hydroxy propyl methyl cellulose (HPMCE5) and Gelucire 44/14, in

pinary and ternary systems.

MATERIALS AND METHODS

Nimodipine (Hangzho Uniwise International Co., Ltd. China)-Polyvinyl pyrrolidine (PVP

40), Hydroxyl propyl methylcelleulose(HPMC)/E5 and Gelucire(44/14) (Sigma- Chem. co.,

USA), Ethanol, dichloromethane, All other chemicals were of extra pure reagent grade and

used as received.

Methods

Preparation of solid dispersion: By solvent evaporation technique NMD(0.25gm) was mixed

with each polymer alone PVP 40, HPMC E5 and Gleucire 44/14 in these ratios (1:1,1:2,1:3)

i.e (0.25:0.25,0.25:0.5,0.25:0.75) drug to polymer respectively to form (F1-F9) in binary

system which are: (Drug:PVP1:1,Drug:PVP1:2, Drug:PVP1:3), (Drug:HPMC1:1,

Drug:HPMC1:2, Drug:HPMC1;3), (Drug:Gelucire1:1;Drug:Gelucire1:2, Drug:Gelucire1:3)

and ternary system (F10-F12) in ratio drug to total polymer (1:1) (NMD,PVP 40 and

Gelucire44/14), (NMD,HPMC E5 and Gelucire 44/14) and (NMD, HPMC E5 and PVP 40)

each formula mixed with ethanol and dichloromethane in ratio 50%:50% and the solvent

were evaporated in open air about 20 minutes untill complete dryness, then the precipitate

was scrapped and ground.

Evaluation and characterization

-(DSC): The DSC thermograms were obtained using DSC-50 differential scanning

calorimeter (shimadzu, seisakusho ltd, Kyoto, japan). Samples (3-4gm) were weighed in

aluminium pans and heated at a scanning rate of 10c /min from 20 to 400 oc in the prescence

of nitrogen at a flow rate of 20ml /min.

Transition temperature (c) and heats of fusion of melting endotherms on the thermograms

were calculated using the DSC t-50 program, wich directly integrates the melting

endothermic peaks giving the heat of fusion (h, joule/g).

-(FT-IR): FT-IR spectra of the drug alone ,and the prepared solid dispersion with FT-IR

Tensor 27 Boker, Germany, was tested at range of 400-4000cm-1. Potassium bromide (KBr)

disc method was used. the samples were ground, mixed thoroughly with KBr and compressed

X- ray Powder Diffractometry: X-ray powder diffraction patterns were recorded on a x-ray

diffractometer (model ysx0104-Holland) using Ni filtered, using a voltage of 39kV, and a

29mA current. The scanning employed was 1minˉˡ over the 4 to 50 diffraction angle (2θ)

range. The relationship used for the calculation of crystallinity was presented by relative

degree of crystallinity.[7]

Drug content determination

Weights equal to 30mg of nimodipine and different weight of the polymers but with different

ratios to form solid dispersion (1:1,1:2,1:3) drug: polymer ratios and mixed with solvent

mixture (ethanol to dichloromethane50:50%) up to 50ml and one ml was taken by

micropipette and completed up to 50 ml with ethanol only and the concentration of the drug

in the solid dispersion was measured with UV apparatus.[8]

In vitro study

1- Dissolution of pure drug as well as solid dispersion of drug were studied using USP,

dissolution apparatusII (Paddle type, Copley, England) accurately weighted amounts of each

formulation equivalent to 60mg of NMD were dispersed over 900ml of the dissolution

medium(Distilled water +0.5%SLS) at 37°c stirred at 50 r.p.m at appropriate intervals,

Samples were withdrawn (5ml aliquot ) over aperiod of 1hour and were replaced by equal

volume of pre warmed medium, the samples were filtered with filter border 0.24µm and

NMD content was determined spectrophot metrically at 237 nm.[8]

2-In vitro dissolution study of capsules of the SD of the optimum formula of ternary

system(NMD,PVP 40 and Gelucire 44/14) were studied using USP, accurately weighted

amounts of each formulation equivalent to 60mg of NMD were kept in capsule and put in

900ml of the dissolution medium(Distilled water +0.5%SLS) at 37°c +0.5 stirred at 50 rpm at

appropriate intervals, samples were withdrawn (5ml aliquot) over a period of 1hour and were

replaced by equal volume of prewarmed medium, the samples were filtered and NMD

content was determined spectrophotmetrically at 237 nm.

All experiments were carried out in triplicate and in the capsule (n=6) and the average was

determined.

RESULTS AND DISCUSSION

Differential scanning calorimetric (DSC)

DSC thermograms of pure drug and corresponding drug polymers system were depicted in

Figure.[8] The DSC curve of Nimodipine shows a sharp endothermic peak (Tpeak =

127.03°C) corresponding to its melting point, indicating its crystalline nature. However, the

characteristic endothermic peak, corresponding to drug melting was broadened and shifted

towards lower temperature, with reduced intensity, in all the formulations used, this could be

attributed to higher polymer concentration and uniform distribution of drug in the polymer,

resulting in complete miscibility of molten drug in polymer. Moreover, the data also indicate

no interaction between the components also suggestes that SD did not induce interaction at

the molecular level and solid dispersion formed is a physical mixture with highly dispersed

drug crystals in a polymer.

FT-IR Study

Figure(9) shows FTIR of NMD alone and its formulations with, PVP 40, HPMC E5, Gelucire

44/14, The distinct bands of NMD appears at characteristic band at3296cmˉ¹, relatedto N-H

stretch, at1694cmˉ¹ associated with the carbonyl bond C=O and at 1496cmˉ¹ representing the

No2group.[10,9]

- FTIR Spectra of PVP 40, the most distinict peak in IR Spectrumof PVP 40 was the

stretching Vibration of the carbonyl gp C=O that would typically appear around

a1650.53cmˉ¹. abroad peak at about 3000- 3700cmˉ¹, (3425cmˉ¹) due to oH stretching

vibration of absorbed water ,2957cm¯¹ due to C—H stretch.

-HPMCE5 alone in which bands were observed at 3443cm-1 (O-H stretching), at

2935cm-1(C---H) stretching, at 1651cm-1(C=O) of the glucose unit and at 1069cm-1(C-O-C

group).[10-9]

-Gelucire 44/14 alone its characteristic peaks at 2923 cm¯¹ and 2862cm¯¹ (C—H stretch),

1736cm¯¹(C=O), 1106cm¯¹ (C---O stretching) and abroad band 3000-4000 due to OH

group.[11]

- F1,F4,F7 shows FTIR of NMD and PVP 40,HPMCE5,Gelucire44/14 in ratio(1:1,) in which

the characteristic peaks of NMD and all polymer were appeared and visible which indicate no

- F10,F11,F12 shows FTIR of NMD and Three polymers in ternary system and in which also

the peaks of all drugs appeared indicate no chemical interaction.

X-ray diffractometry

(XRD) spectra was performed to optimum formula SD (Figure10) of (NMD,PVP 40 and

Gelucire44/14), The x-ray diffractogram of NMD has sharp peaks at diffraction angles (2θ)

6.4°,12.87°,20.28°,17.36° and 19.70,°. It is showing a typical crystalline pattern. However,

the major peaks of drugs were absent with SD this indicates that the drug is converted in to

the amorphous form.

Drug content study

The drug content of the prepared formulations of Nimodipine was observed to be varying

from 98-100% showed in table 1.

Table 1: Drug content in the prepared formulations Sr.NO.

Drug F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Drug content(%) (±SD),n=3

98.4±0.4 98.7±0.3 99.2±1.0 99.3±0.8 100.01±0.3 100.08±0.4 100.03±0.2 99.2±1.2 99.55±0.5 100.05±0.4 100.03±0.2 100.01±0.5 100.06±0.3

In vitro studies

1- Table no(2) and figures (1-6)shows in vitro Release of NMD from its SDs, It was observed

that all formulations show the increase in the % release of the drug with increase in polymer

ratio in binary system, in ternary system the optimum formulation was F10(NMD,PVP 40

and Gelucire 44/14). It was observed that the formulation F-10 showed the most increase in

the %release of the drug from the formulations which is to be kept in the capsule. The

formulation F-12(NMD,PVP -40 and HPMCE5) Showed the lesser % release of the drug in

2-In vitro Release of NMD from its SD kepted in capsule

The in vitro release of NMD from prepared capsules (n=6) is presented in table (3) and figure

(7) it is obvious that the release is affected by both the solubilizing effect of PVP 40 and

Gelucire 44/14 on the drug and the percent of polymers in the SD which contriputed to

increased solubility and dissolution in the aqueous medium.

By Polymers (PVP 40 and Gelucire44/14) in this ratio drug to total polymers(1:1)resulted in

rising and increasing the in vitro drug release.to be 94.3% at 20 minutes.

Effect of different Polymers on the dissolution of Nimodipine

SDs were performed include. Incorporation of polymer (HPMCE5, PVP 40, Gelucire 44/14)

enhanced the dissolution rate of nimodipine. in addition the properties of the drug is

improved. The enhancement of dissolution of drug from drug polymer systems can be

ascribed to several factors. The mechanism of dissolution rate improvement from solid

dispersion is lack of crystallinity and particle size reduction considered to be important

factors for dissolution rate enhancement. Mixing of drug with a hydrophilic polymers results

in greater wetting and increase surface available for dissolution by reducing interfacial

tension between the hydrophilic drug and dissolution media. It was noted that drug polymer

system sink immediately, while pure drug keeps floating on the surface for a longer time

interval.[12] The dissolution parameters of drug (nimodipine) solid dispersion with various

polymers (HPMCE5), PVP -40, Gelucire44/14) in same concentration of each polymer. The

dissolution rate of pure drug is low as 22.3% of the drug gets dissolved 60min respectively.

Solid dispersions formulated with all the polymers exhibited significant improvement in the

dissolution parameters of drug. The increase in the dissolution rate of the solid mixtures

might be due to size reduction and increase in the wettability of the drug molecules in

presence of the polymers. Polymers also lowering the surface tension, hence increasing the

solubilizing effect. This kind of technique can be extended for improvement dissolution rate

of drug showing poor dissolution profiles and causing erratic bioavailability.[13] The present

invention often produces particles having reduced crystallinity as compared to the bulk drug,

Table 2: Amount Released of NMD from Different Formulations.

Sr .no Amount released of NMD in (%)(n=3)

Time(m) Drug F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 10 10±0.27 75±0.24 89±1 96±0.3 61±0.23 61±0.4 75±0.5 20±0.32 25±0.65 33±0.31 95±0.38 85±0.4 44±0.5 20 13±0.35 88±0.00 100±.0.26 100±0.5 68±0.3 73±0.39 84±0.2 22±0.6 27±0.32 39±0.20 100. ±0.24 99.60±0.43 64±1 30 16±0.3 100±.0.7 100.13±0.7 100±0.35 69±0.43 87±0.23 95±0.6 24±0.5 28±0.51 42±0.24 100.2±0.22 100.08±0.3 78±0.25 45 19±0.4 100±.0.3 100.48±0.4 100±0.4 71±0.2 89±0.5 98±0.32 26±0.24 29±0.23 43±0.43 100±.0.31 100±0.00 91±0.87 60 22±0.21 100.12±0.45 100.95±0.3 100.79±0.36 78±0.3 96±0.29 99±0.38 31±0.65 31±0.49 44±1 100±0.32 100.91±0.5 99.75±0.23

Table no(3): Amount of drug released from prepared capsules Time

(min)

Amount of NMD released in %(n=6) 3 5 6 10 15 20 22 0+0.00 0+0.00 8.4+0.32 55+0.5 77.69+1 94.3+0.6 100+0.45

Figure (2) Dissolution of NMD and HpmcE5 1in different ratios (1:1,1:2,1:3) in relation to pure Drug

Figure (3) Dissolution NMD and Gelucire44/14in different ratios (1:1,1:2,1:3) in relation to pure Drug

Figure (5): Dissolution NMD and (HPMC E5 & Gelucire 44/14) in relation to pure Drug

Figure (6): Dissolution NMD and (PVP 40 & HPMCE5) in relation to pure Drug

N=6

Nimodipine

Figure 8: DSC Thermograms of different Formulations of NMD

Figure(10) shows X-ray diffraction of :

(A) Nimodipine

(B) PVP 40

(C) Gelucire44/14

(D) Solid dispersion (PVP 40 & Gelucire 44/14)

CONCLUSION

From the present study, it can be concluded that the hydrophilic polymers played an

important role to enhance the dissolution rate. Among all the formulations F10 that contain

PVP 40 and Gelucire44/14 as a carrier was better one shows 95% drug release in 10 minutes.

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