International Journal of PharmTech ResearchCODEN (USA): IJPRIF ISSN : 0974-4304

Vol.2, No.1, pp 950-959, Jan-Mar 2010

Evaluation of Some Novel Techniques ForDissolution Enhancement of Poorly Water Soluble

Drug Nimodipine

Sanjeev Kumar1*, Pradeep Kumar2, Chanderparkash3, Shailendra K Singh4

1Guru Gobind Singh College of Pharmacy, Yamunanagar-135001, Haryana, India

2Chitkara College of Pharmacy, Chandigarh-Patiala National Highway,Rajpura-140401, Patiala, Punjab, India.

3G. V. M. College of Pharmacy, Gohana Road, Sonipat-131001, Haryana, India.

4Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science andTechnology, Hisar-125001, Haryana, India.

*Corres. author: skgothwal@yahoo.co.inPhone: +91-9255445645

Abstract: Nimodipine (NMP), a Ca++ channel blocker, has a low oral bioavailability due to poor solubility andinsufficient dissolution rate. In order to improve the same, various techniques were employed viz., evaporative precipitationinto aqueous solution (EPAS), spherical agglomeration (SA) and solid dispersion using solvent evaporation and melt-mixing. Formulations so prepared were characterised by differential scanning calorimetry (DSC) and X-Ray powderdiffractometry (XRD) and were investigated for drug content studies, solubility studies, in-vitro study and in vivoevaluation of anti-inflammatory activity. The formulations of NMP prepared by spherical agglomeration technique have thegood drug content and the formulations with SLS and HPMC show a significant increase in solubility in case of SAtechnique. In case of solid dispersion, all carriers show improvement in the dissolution rate of the drug The DSC studiesshow no change in the polymorphism in most of the formulations The XRD studies of the formulations show no change intheir crystalline form..Keywords: Nimodipine, evaporative precipitation into aqueous solution, spherical agglomeration, solid dispersion,dissolution.

INTRODUCTIONPoor aqueous solubility of drugs is a major limitingfactor with many new drugs in their successful launch inmarket in spite of their potential pharmacokineticactivity. Poor solubility (less than 10 %) of a drug, leadsto poor dissolution in the gastro intestinal tract (GIT)hence, incomplete and erratic absorption ultimatelylimits its clinical utility. Further, poorly soluble drugsare generally administered at much higher doses thanthe actual dose in order to achieve necessary drugplasma levels leading to increased adverse reaction &cost of therapy and often yields erratic pharmacologicalresponse and hence poor patient compliance. About 40

% of drugs being in the pipeline of pharmaceuticalcompanies are poorly soluble, which emphasizes theneed of a technique to overcome such problems.1 Poorlywater-soluble drugs are associated with slow drugdissolution followed by slow absorption leadingeventually to inadequate and variable bioavailability.Solubilty, one of the key parameter in BCS, as well asdissolution rate is the most essential fators controllingthe rate and extent of drug absorption. A poorly watersoluble compound is defined which get soluble lessthan 1part per 10000 part of water. A poorly watersoluble drug, more recently, has been defined in

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general terms which require more time to dissolve inthe gastrointestinal fluid than it take to be absorbed inthe gastrointestinal tract. Thus a greater understandingof dissolution and absorbation behaviors of drugs withlow aqueous solubility is required to successfullyformulate them into bioavailable drug products.2

Nimodipine (NMP), a Ca++ channel blocker, wasselected as model drug as the drug has low aqueoussolubility where its GIT absorption is limited by itsdissolution in the gastrointestinal fluids exhibiting alow bioavailability after oral administration.3 Anumber of approaches are practiced to improve theaqueous solubility poorly soluble drugs viz., soliddispersion (solvent evaporation method, fusion processmelt- mixing, freeze-dried, fusion-solvent method,kneading technique, co precipitation),4 sphericalagglomeration,5 evaporative precipitation in aqueoussolution,6 microcrystallisation,7 supersaturation,8 prodrug approach,9 polymorphism,10 complexation,11 phadjustment,12 co-solvents,13, 14 use of surfactant,15 andparticle size reduction.16 These techniques result intopolymorphic changes or changes in crystal structure orhydrophilicity or particle size changes due toformation of molecular dispersion. The formulationswere evaluated by the evaluation techniques utilizedalso focused on studying these changes in drugs alongwith their solubility, dissolution and other properties.The solubility and in vitro study was evaluated by thespectrophotometer in the dissolution media. Thepolymorphic form of the formulation is evaluated bythe differential scanning calorimetry (DSC) & crystalstructure determination by the powder X-raydiffraction studies (XRD) at the different angles. In thepresent investigation the techniques utilized wereEvaporative Precipitation into Aqueous Solution,Spherical agglomeration, Solvent evaporation andMelt-Mixing, mainly due to their ease in formulationand versatility in application. All these techniques canbe easily accommodated at industrial level and thetechniques can be easily incorporated in formulationoperations in pharmaceutical industry.

MATERIALS AND METHODSMaterialsNimodipine was obtained as gift sample from U.S.Vitamins Ltd., Mumbai, India. Polyvinyl pyrrolidoneK30 (PVP), Hydroxypropylmethylcellulose (HPMC)and Poly Ethylene Glycol (PEG-4000) were purchasedfrom Qualigens Fine Chemicals (Mumbai, India). Allother chemicals were of extra-pure reagent grade andused as and when received.

MethodsPrepration of spherical agglomerates of PEG-4000,HPMC, SLS, PVPNMP (2.5 g) was dissolved in 40 mL DMF by gentlewarming up to 50ºC and then cooled to roomtemperature. A solution of 0.1% w/v of

surfactant/polymer (HPMC, PEG-4000, SodiumLauryl Sulfate, PVP K-30) in distilled water (30 mL)was then added to drug solution in DMF with stirring(Table 1). The precipitated solid was dissolved byfurther addition of 30 mL DMF and gentle warming.This solution was added with stirring to 400 mLdistilled water contained in the agglomerating vessel.Chloroform (18 mL) was added drop wise with stirringat 900 rpm for 30 minutes. The precipitate obtainedwas collected and dried in vacuum and stored indesiccator further studies.

Preparation of solid dispersion by solventevaporation techniqueIn this technique the proper volume of two solutionswere to be taken. NMP (5 wt %) and polymerPEG/SLS/HPMC/PVP (5 wt %), in ethanol weremixed and the mixtures were stirred for 10 minutes at900 rpm (Table 1). The final solutions were pouredonto Petri dish and the solvent was left to evaporate inopen air for 2 days. After complete removal of thesolvent the solid dispersions were stored at ambienttemperature in desiccator.

Preparation of hydrophilic coated drug particles byevaporative precipitation in aqueous solution(EPAS) methodPreheated (@70ºC) organic solution of the NMP inChloroform (1%) is sprayed though a fine nozzle into apreheated (@70ºC) (1%) aqueous solution ofsurfactant/polymer. The rapid evaporation of theorganic solvent produces high supersaturation andrapid precipitation of the drug in the form of acolloidal suspension that is stabilized by a variety oflow molecular weight surfactant/polymer solution of(SLS, PEG-4000, PVP, and HPMC). The suspensionswere then freeze dried (Table 1).

Preparation of solid dispersions by melt mixingmethodA physical mixture of NMP and PEG were heatedduring stirring in a reaction tube immersed in an oilbath to 130°C. When the drug was completely meltedand a homogeneous solution was obtained. Soliddispersions with Drug/PEG 20/80, 40/60, 60/40 weightratios were prepared (Table 1). Next, the tubes wereimmersed in a water bath to quench the melt. Theprepared samples were dried and stored at 25°C indesiccator.

EVALUATION AND CHARACTERIZATIONDifferential Scanning CalorimetryDSC studies of the prepared samples were conductedimmediately after preparation as well as after storagefor 6 months. A (Q-10, TA) Instrument equipped withan intraocular 2p cooling accessory was used. Samplesof 10mg to 5mg were placed in saturated aluminum

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pans and sealed with a lid. Heating scans by 10ºC /minapplied with a purge of 50ml/min. Fast heating ratesare preferred to prevent changes during scanning.

X-Ray Powder DiffractometryX-ray powder diffraction patterns were recorded on aXPERTO-PRO x-ray diffractometer using Ni filtered,using a voltage of 45kV, and a 40mA current. Thescanning employed was1 min- 1 over the 6 to 50diffraction angle (2θ) range. The relationship used forthe calculation of crystallinity was presented byrelative degree of crystallinity. 17

Relative degree of crystallinity (RDC) =ref

sam

II

where,Isam= Peak height of the sample under investigationIref = Peak height at the same angle for the referencewith the highest intensity.

Drug Content StudiesThe individual formulations equivalent to 10mg ofdrug were weighed accurately and mixed with 100 mlof methanol. After that the solutions is to be 10 timesdiluted with methanol. The suspension was filteredthrough 22µm nylon disc filter and drug content wasanalyzed at 237nm UV spectrophotometer (PerkinElmer EZ301, USA).

Solubility StudiesIn solubility study of the drug and its formulations wasdone by shaking 10 mg of Std. drug and itsformulations (equivalent to 10 mg drug) with 40ml ofdistilled water (0.1%) in 100ml volumetric flask for 24hours on water bath shaker. And then make up thevolume up to 100ml. After 10 times dilution thenfiltering and determining spectrophotometrically at237nm.

In Vitro StudyThe dissolution study is to be done of the10 mg of Std.drug and its formulations (equivalent to 12 mg drug).Formulations (10mg) of Nimodipine were placed incapsule with 200 mg sprayed dried lactose in a rotatingbasket (USP XXII) and then placed in 900 ml 0.1%SLS solution and stirred at a speed of 50 rpm withtemperature maintained at 37 ± 1ºc. Aliquots of 10mlwere withdrawn at appropriate time intervals and anequal volume of 0.1%SLS was replaced in the vessel.Nimodipine in the aliquot was assayed spectrophotometically at 237nm.

RESULTS AND DISCUSSIONDifferential scanning calorimetric (DSC) studyDSC thermograms of pure drug and correspondingdrug carrier system are depicted in Figure 1. The DSCcurve of Nimodipine (NMP-16) shows a sharp

endothermic peak (Tpeak = 126.03°C) correspondingto its melting, indicating its crystalline nature.However, the characteristic endothermic peak,corresponding to drug melting was broadened andshifted toward lower temperature, with reducedintensity, in all the formulations of NMP-01, NMP-07,NMP-012, and NMP-13. This could be attributed tohigher polymer concentration and uniform distributionof drug in the crust of polymer, resulting in completemiscibility of molten drug in polymer. Moreover, thedata also indicate there seems to be no interactionbetween the components of binary system. Nosignificant difference in DSC pattern of dispersionsand physical mixture suggests that even in thekneading process could not induce interaction at themolecular level and solid dispersion formed is aphysical mixture with highly dispersed drug crystals incarrier.

X-ray Diffraction StudyX-ray diffractometry (XRD) spectra of pure compoundand binary systems with carriers are presented infigure 2. The x-ray diffractogram of NMP-16 has sharppeaks at diffraction angles (2θ) 6.54°, 12.87°, 20.28°,17.36°, and 19.70º. It is showing a typical crystallinepattern. However, all major characteristic crystallinepeaks appear in the diffractogram of all theformulations (NMP-01, NMP-07, and NMP-12). TheRDC values of NMP-01, NMP-07 and NMP-12) were0.8281, 1.056 and 0.2239 respectively. Moreover, therelative intensity and 2θ angle of these peaks remainspractically unchanged.

Drug content studyThe drug content of the prepared formulations ofNimodipine was observed to be varying from 88.4 to15.1% and it was maximum with formulation (NMP-02) and minimum in formulation (NMP-11) as shownin Table 2. This studies shows that sphericalagglomeration technique shows the maximum drugcontent and the evaporative precipitation in aqueoussolution (EPAS) show the minimum drug content.

Solubility studiesFor Nimodipine the aqueous solubility of drug wasobserved to be maximum in the NMP04 formulation isabout (6.11±0.02 ug/ml) and is (1.85±0.03 ug/ml) inthe NMP02 formulation as shown in Table 2 andFigure 3. Studies shows that spherical agglomerationtechnique shows the maximum drug solubility withSLS surfactant and with PVP this technique showminimum drug solubility. In the solid dispersion(solvent evaporative) technique the formulationNMP08 show the greater (5.49±0.02 ug/ml) andformulation NMP05, NMP06 & NMP07 show theslightly more solubility. In the EvaporativePrecipitation technique in Aqueous Solution theformulation NMP12 show the maximum formulation

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NMP-10 shows minimum solubility (4.51±0.04 &2.11±0.06 ug/ml respectively) as compared to theNMP16. In the solid dispersion (Melt Mixing)technique the formulations (NMP13) show the(3.31±0.03 ug/ml). Over all in the solubility studiesshow that the spherical agglomeration technique andEPAS is the best method for the increases in thesolubility of the nimodipine with SLS.

In vitro dissolution studiesIn vitro dissolution studies of the preparedformulations were done on USP-1 apparatus usingbaskets. The specifications used for dissolution studyof the all the prepared formulations were same anddescribed below. In all the formulation, the drugcontent was taken as 10 mg per capsule in 900 mldissolution medium, 37˚C containing SLS (0.5 % w/v)and at different time intervals, 10ml of the solutionwas withdrawn until 16 hr.InVitro dissolution study of the different formulationsof Nimodipine prepared by spherical agglomerationtechnique, it was observed that the formulationNMP04 show the increase in the %release of the drugfrom the formulation which are to be kept in thecapsule as compared to the std. drug profile. Theformulation NMP-02 Show the lesser % release of thedrug in the dissolution medium.In Solid Dispersion (Solvent Evaporation) technique, itwas observed that the all formulation NMP-05, NMP-06, NMP-07, NMP-08 show the increase in the%release of the drug from the formulations. In(EPAS) technique, it was observed that theformulation NMP-12 show the increase in the%release of the drug from the formulation which are tobe kept in the capsule as compared to the std. drugprofile. The formulation NMP-09 Show the lesser %release of the drug in the dissolution medium. In SolidDispersion (Melt Mixing) technique, it was observedthat the formulation NMP-13 show the maximumincrease in the %release of the drug from theformulation which are to be kept in the capsule ascompared to the std. drug profile. The formulationNMP-15 Show the lesser % release of the drug in thedissolution medium as compared to the std. drugrelease profile as shown in Figure 4 - Figure 7 andTable 2.

Effect of different carriers on the dissolution ofNimodipineSpherical agglomeration techniques were developedfor improving the solubility of microcrystallinenimodipine. The process involved agglomeratingmicrocrystal using agglomerating solvents. Temp andspeed of agitation were optimized to obtain sphericalagglomerates in a desired range, which was found tobe essential to enhance the solubility. Incorporation ofpolymer/surfactant (HPMC, SLS) duringagglomeration significantly enhanced the dissolution

rate of nimodipine. In additional flow andcompressibility properties of the drug is improved.The enhancement of dissolution of drug from drugcarrier systems can be ascribed to several factors. Themechanism of dissolution rate improvement from soliddispersion is lack of crystallinity and particle sizereduction considered to be important factors fordissolution rate enhancement. Mixing of drug with ahydrophilic carrier results in greater wetting andincrease surface available for dissolution by reducinginterfacial tension between the hydrophilic drug anddissolution media. It was noted that drug carriersystem sink immediately, while pure drug keepsfloating on the surface for a longer time interval.18

The dissolution parameters of drug (nimodipine) soliddispersion with various carriers (HPMC, PVP K-30,PEG-4000, SLS) in same concentration of each carrier.The dissolution rate of pure drug is low even in thesurfactant based medium, as 22.3 % of the drug getsdissolved 360 min respectively.Solid dispersions formulated with all the carriersexhibited significant improvement in the dissolutionparameters of drug. The order of dissolutionenhancement with various binary systems was found tobe (NMP-08>NMP-06>NMP-07>NMP-05) fornimodipine. The increase in the dissolution rate of thesolid mixtures might be due to size reduction andincrease in the wettability of the drug molecules inpresence of the surfactants. Surfactants also loweringthe effect of surface tension, hence increasing thesolubilizing effect. This kind of technique can beextended for improvement dissolution rate of drugshowing poor dissolution profiles and causing erraticbioavailability.19

In evaporative precipitation into aqueous solution(EPAS) to form micron to sub-micron sized particles,leading to increased bioavailability relative to largerparticles. Soluble stabilizers offer the ability to formsubmicron particles that have high dissolution rates inaqueous media. The present invention often producesparticles having reduced crystallinity as compared tothe bulk drug, which enhances dissolution.20

CONCLUSIONSpherical agglomeration is a better technique for thesolubility enhancement of Nimodipine because thedrug loaded to the carriers in very significant amountsdue to which the bulkiness of the dosage form isreduced and the solubility and oral bioavailability ofthe drug improved nearly twice the pure drug. TheEPAS techniques also gave better results in the in vitrostudies but their limitation is that the drug content inthe formulations is very less, so it enhances thebulkiness of the dosage form. Present investigationsuccessfully enhanced the solubility and dissolutionprofile of the investigational drug there by enhancingthe bioavailability of drugs and improving the patientcompliance.

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TABLE 1: COMPOSITION OF VARIOUS FORMULATION BATCHES DEPENDING ON THE TECHNIQUES

TABLE 2. CONTENT, SOLUBILITY AND % RELEASE OF NIMODIPINE FROM DIFFERENTFORMULATIONS IN COMPARISON WITH ORIGINAL DRUG.

Sr.No. Formulations % drug content Solubility(µg/ml)

% drug releasedafter 6 hrs

1 NMP-01 85.7±0.55 4.03±0.04 39.82 NMP-02 88.4±0.30 1.85±0.03 20.53 NMP-03 79.3±0.50 2.02±0.03 20.24 NMP-04 83.5±0.50 6.11±0.02 45.75 NMP-05 64.5±0.20 4.01±0.04 31.36 NMP-06 49.5±0.40 3.15±0.01 56.87 NMP-07 49.9±0.30 3.53±0.02 45.78 NMP-08 47.2±0.40 5.49±0.02 59.69 NMP-09 50.7±0.50 2.43±0.03 22.1

10 NMP-10 40.0±0.10 2.11±0.06 25.311 NMP-11 15.1±0.20 2.32±0.06 35.612 NMP-12 26.2±0.40 4.51±0.04 59.413 NMP-13 35.6±0.40 3.31±0.03 35.214 NMP-14 40.2±0.20 2.88±0.02 21.215 NMP-15 51.0±0.30 2.45±0.04 19.316 NMP-16 100±0.00 2.68±0.03 22.3

Sr. No. Formulations Techniques Solvent Polymers/Surfactant1 NMP-01 SA DMF HPMC2 NMP -02 SA DMF PVP3 NMP -03 SA DMF PEG-40004 NMP -04 SA DMF SLS5 NMP -05 SE Ethanol HPMC6 NMP -06 SE Ethanol PVP7 NMP -07 SE Ethanol PEG-40008 NMP -08 SE Ethanol SLS9 NMP -09 EPAS Chloroform HPMC10 NMP -10 EPAS Chloroform PVP11 NMP -11 EPAS Chloroform PEG-400012 NMP -12 EPAS Chloroform SLS13 NMP -13 MM NO PEG-400014 NMP -14 MM NO PEG-400015 NMP -15 MM NO PEG-400016 NMP -16 STD NO NO

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Figure 1: DSC thermogram of pure Nimodipine and its formulations.

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Figure 2: Powder X-ray diffraction spectra of pure Nimodipine (NMP-16), NMP-01, NMP-07 and NMP-12.

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0

1

2

3

4

5

6

7

NMP01

NMP02

NMP03

NMP04

NMP05

NMP06

NMP07

NMP08

NMP09

NMP10

NMP11

NMP12

NMP13

NMP14

NMP15

NMP16

Formulations

Con

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ratio

n (u

g/m

l)

Figure 3: Solubility studies of Nimodipine (NMP 16) and its formulations.

05

101520253035404550

0 50 100 150 200 250 300 350 400

Time (min)

% D

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ase

NMP 1 NMP 2 NMP 3 NMP 4 NMP 16

Figure 4: Dissolution profile of pure nimodipine (NMP 16) and its formulations preparedby spherical agglomeration (NMP 1 – NMP 4).

0

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0 50 100 150 200 250 300 350 400

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Figure 5: Dissolution profile of pure nimodipine (NMP 16) and its formulations preparedby solvent evaporation (NMP 5 – NMP 8).

Sanjeev Kumar et al /Int.J. PharmTech Res.2010,2(1) 958

0

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30

40

50

60

70

0 50 100 150 200 250 300 350 400

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Figure 6: Dissolution profile of pure nimodipine (NMP 16) and its formulations prepared byevaporative precipitation into aqueous solution (NMP 09 – NMP 12).

0

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Figure 7: Dissolution profile of pure nimodipine (NMP 16) and its formulations prepared bymelt mixing (NMP 13 – NMP 15).

ACKNOWLEDGEMENTThe authors express their thanks to the CentralAnalytical Instrumentation Laboratory, PanjabUniversity, Chandigarh for XRD studies.

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