Enhancement of Dissolution Rate and Formulation Development of Efavirenz Capsule Employing Solid Dispersion Method

 

Ashok A. Hajare*, Udaykumar T. Kashid, Pravin Walekar and Pravin M. Hajare

Dept. of Pharmaceutical Technology, Bharati Vidyapeeth College of Pharmacy, Kolhapur-416013, MS, India

 

ABSTRACT:

The research work was undertaken to improve dissolution rate of efavirenz (EFA). It has low aqueous solubility and low intrinsic dissolution rate. The solid dispersions were prepared by fusion method using 1:4(70%),1:4(80%), 1:8(70%) and 1:8(80%) ratio of EFA to the mixture of polyethylene glycol 400 (PEG) and polysorbate 80 (PS).The solid dispersions were characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Dispersions were evaluated to determine drug content, practical yield and invitro drug release. The DSC thermogram of solid dispersion showed complete amorphization of drug. FTIR study revealed absence of any chemical interaction between EFA and excipients solid dispersion. Solubility of EFA in solid dispersion was increased in distilled water. The drug content was found to be high. The invitro dissolution studies showed marked increase in the dissolution rate than pure drug. The dispersion with 1:8, 80% of EFA and PEG showed faster dissolution rate. The feasibility of packing solid dispersion into capsule was also investigated. Capsule employing pure EFA and EFA solid dispersion were evaluated. Capsules with solid dispersions showed rapid and higher dissolution rate. The study revealed enhancement of dissolution of the EFA by PEG when formulated as solid dispersion.

 

 

INTRODUCTION:

The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastro-intestinal (GI) fluids often cause insufficient bioavailability. Especially for BCS class II drugs the bioavailability may be enhanced by increasing the solubility and dissolution rate in the GI fluids¹. This may be achieved by incorporating drug in hydrophilic carrier material. Moreover, these drugs despite their high permeability are only absorbed in the upper small intestine. Consequently, if these drugs are not completely released in the upper gastro intestinal tract (GIT), they have low bioavailability. Often poor drug dissolution or solubility rather than limited permeation through the epithelia of the GIT are responsible for low oral bioavailability. Thus aqueous solubility of any therapeutically active substance is a key property, as it governs dissolution and absorption and thus the in vivo efficacy².

 

Solid dispersion (SD) was first introduced to overcome low bioavailability of lipophilic drugs by forming eutectic mixtures of drug with water-soluble carriers³. Today it has been used for a variety of poorly soluble drugs. The term SD refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles⁴. SD is defined as a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent, or melting solvent method. The higher dissolution rates of drugs from SDs can be ascribed to formation of higher energy metastable states of the components, proportion of carrierpresent⁶, reduction of particle size, increased solubilization and formation of amorphous forms of drug and carriers⁵. The wettability is greatly increased due to the surfactant property of the polymer resulting in decreased interfacial tension between the medium and the drug. The mechanisms involved include inhibition of crystal growth by carrier polymers⁵, co-solvent effect on the drug by the water soluble carriers⁷, intermolecular hydrogen bonds between drug and carrier⁹ and local solubilization effect of carrier at the diffusion layer⁸. SD in which the drug is dispersed in solid water-soluble matrices either molecularly or as fine particles have also shown promising results in increasing bioavailability of poorly water-soluble drugs.

The commercial use of SD systems has been limited primarily because of manufacturing difficulties and stability problems⁵. Some of the manufacturing problems with SD systems may be overcome by using surface active and self-emulsifying carriers. The carriers are melted at elevated temperatures, the drugs are dissolved in molten carriers, and the hot solutions are filled into hard gelatin capsules. Solid plugs are formed inside capsules at room temperature, and due to the surface activity of carriers, drugs dissolve or disperse rapidly once the plugs come in contact with the GI fluid⁹. Some of the examples of bioavailability improvement by SD include paracetamol¹⁰, gliclazide¹¹, and meloxicam¹². Excipients such as PEG a hydrophilic polymer and PS a surfactant are utilized for this purpose^13-14. The fusion method is sometimes referred to as the melt method, which is correct only when the starting materials are crystalline¹⁵. The fusion method has serious limitations such as it can only be applied when drug and matrix are compatible and mix well at the heating temperature^9,11 and when the drug-matrix miscibility do not change during cooling^{16, 17}.

 

In this study SDs of EFA were prepared with PEG and PS by fusion method. Reduced crystalline structure and improved wettability were the probable mechanisms by which PEG can enhance dissolution from SDs. The PEG-polysorbate carriers have been found to enhance dissolution and bioavailability of drugs from the SDs^{18, 19}. Direct filling of hard gelatin capsules with the liquid melt of SDs avoids grinding-induced changes in the crystallinity of the drug. The filling of hard gelatin capsules has been feasible in molten dispersions of EFA-PEG.

 

MATERIALS AND METHODS:

EFA was obtained as a gift sample from Emcure Pharmaceuticals Ltd, Pune. PEG and PS were procured from commercial sources. All other chemicals and reagents were of pharmacopoeial grade.

 

Table 1: Formulation plan of EFA solid dispersions

 

Preparation of solid dispersion

The fusion method was used for the preparation of SDs. SDs were prepared by melting PEG in specific proportion of PS to form a melt followed by addition of accurately weighed quantity of EFA to produce a completely saturated form. The composition used to prepare SDs of EFA in PEG-PS mixtures are given in Table 1. The mixtures were heated with continuous stirring under controlled temperature to melt drug and carrier. The molten dispersions were immediately transferred to ice bath to solidify. The SDs prepared were pulverized and sifted through 20# and stored in desiccators.

 

Evaluation of solid dispersion

SDs of EFA were evaluated for their practical yield and solubility. The SDs showing good solubilities were evaluated for various parameters listed in Table 2. Many attempts have been made to investigate the molecular arrangement in SDs⁵. However, most effort has been put into differentiate between amorphous and crystalline material. Many modern techniques are available that detects the amount of crystalline material in the dispersion. The amount of amorphous material is never measured directly but is mostly derived from the amount of crystalline material in the sample. The properties of a SD are highly affected by the uniformity of the distribution of the drug in the matrix. The stability and dissolution behavior could be different for SDs that do not contain any crystalline drug particles.

 

Table 2: Evaluation parameters and techniques used to study solid dispersion

 

Practical Yield

Percentage practical yield was calculated to know about percent yield thus it helps in selection of appropriate method of production. Practical yield (PY)²⁰ was calculated using equation (1).

 

PY (%)	=	Practical Mass (SD)	………(1)
		Theoretical Mass (Drug + Carrier)

Saturation solubility

The excess amount of the SD was added to glass stoppered test tubes containing 10 mL of distilled water and subjected to shaking on a rotary shaker for 24 h at 37°C. These solutions were centrifuged at 4000 rpm for 10 min and supernatant was filtered through filter. Accurately measured aliquots were withdrawn from the filtered solution and analyzed after appropriate dilution with distilled water and compared with pure drug solubility.

 

Drug content

Stock solutions were prepared by dissolving SD equivalent to 10 mg of EFA in 10 mL methanol. Accurately 1 ml of stock solution is diluted with methanol to 100 mL. The solution was filtered, suitably diluted and absorbance was observed at 245nm by using UV visible spectrophotometer. The drug content was calculated using the equation (2).

 

 

% Drug content	=	Actual amount of drug in SD	…(2)
		Theoretical amount of drug in SD

 

 

Dissolution Rate Study

Dissolution profiles of pure EFA and EFASDs and EFA in capsule were studied in 900 mL distilled water containing 2% Sodium lauryl sulphate (SLS) employing USP Dissolution Test Apparatus Type II (Lab India Disso 8000) at 50 rpm. The SLS was added to maintain sink condition. Tested materials were 10mg of pure EFA, EFA SD equivalent to 10 mg, and a capsule containing 50 mg EFA. A temperature 37±0.5ºC was maintained in each test. Aliquots of 5 mL were withdrawn and filtered through membrane filter (0.45μ) at intervals of 5, 10, 15, 30, 45 and 60 min and assayed for EFA content at λ_max 245 nm.

 

Infrared spectrum analysis

IR spectra of pure EFA and EFASDs were obtained by a Shimadzu FTIR spectrophotometer using KBr pellets. KBr pellets were prepared by gently mixing the sample with KBr (1:300). Dry KBr was finely ground in mortar and samples were subsequently added and gently mixed in order to avoid trituration of the crystals. A manual press was used to form the pellets. The scanning range used was 4000 to 400 cm^-1.

 

DSC study

The pure drug and SDs were examined by DSC (Model Q100, TA Instruments New Castle, USA). Samples of about 5-10 mg were hermetically sealed in aluminum pans and heated at a constant rate of 10°C/min over a temperature range of 25–200°C. An inert atmosphere was maintained by purging with nitrogen gas at a flow rate of 100 mL/min. An empty aluminum pan was used as reference.

 

PXRD study

The XRPD measurements of the SD were performed on a Philips PW 1830 X-ray generator with a copper anode (Cu Kα radiation, λ = 0.15418 nm, 40 kV), fixed with a diffraction control unit. The radiation scattered in the crystalline regions of the samples was measured. Patterns were obtained using a step width of 0.02º with a detector resolution in 2θ between 4º and 40º at ambient temperature.

 

RESULTS AND DISCUSSION:

Practical Yield:

Practical yield gives an idea about effectiveness of method and thus help in selection of appropriate production method. The results of percent practical yield (%PY) studies are shown in Fig. 1. %PY for all SD formulations was 85.50% -97.70%. Highest yield 97.70% was observed for SD4. Observations revealed that the selected method to produce SD was effective with sufficient and reproducible yield. Percent yield shows its efficacy towards large scale production.

 

Saturation Solubility:

The results of solubility study are given in Fig. 2. The observations revealed that the SD with different carrier proportions and drug: carrier ratios showed proportional increment in the solubilities compared to pure EFA. It may be attributed to the improved porosity, decreased primary particle size and partial amorphization of EFA in dispersed state compared to its raw crystals. This may also be due to the improved wettability of dispersions.

 

Figure 1: Comparative %PY of SDs

 

 

Figure 2:  Comparative saturation solubility of EFA in pure form and in SDs

 

 

Figure 3:  Percent EFA content in SD

 

Percent Drug Content:

The drug content, Fig. 3, was found in the range of 75.34% to 106.02%. The increased drug recovery was relative to the amount of carrier and surfactant mixtures. In SD4 the EFA might be uniformly dispersed in the powder formulation. Although drug content was good in SD4 other SDs were also shown comparable drug contents and thus the method used in this study appears to be appropriate for formulating SDs. All the EFA capsules studied contained the EFA about 100±2% of the theoretical yield.

 

Dissolution study:

The dissolution rate of SDs, Fig. 4, showed that the cumulative percentage drug release of batch SD2 and SD4 were almost similar and significantly greater than SD1 and SD3. The results indicate SD4 as an optimized composition.

 

SD of EFA, Fig. 5, showed superior dissolution properties when compared to EFA pure drug. The feasibility of formulating EFA as SD using PEG in capsules showed rapid and higher dissolution rate. The dissolution profiles revealed that the polymer-surfactant ratio play critical role in solubility enhancement. The SD formulated as SD4 showed highest dissolution rate.

 

FTIR study:

The FTIR spectra of the pure EFA andits SD, Fig. 6, were recorded in the wavelength range of 4000 to 400 cm^-1. It shows characteristic peak at 3363 cm^-1, 3052 cm^-1, 2944  cm^-1, 2300 cm^-1, 1691 cm^-1, 1602 cm^-1, 1217 cm^-1 and 1326 cm^-1 attributed to N-H stretching vibrations, aromatic C-H stretching vibrations, aliphatic C-H stretching vibrations, C≡C cm^-1 stretching vibrations, C=O stretching vibrations, C=C stretching vibrations, C-F stretching vibrations, C-O-C stretching vibrations, respectively. Physical mixture of EFA shows all the characteristic peaks of EFA indicating absence of any interaction between the EFA and  carriers.

Figure 4:  In vitro dissolution profile of EFA in pure form and in its SD.

 

Figure 5:  In vitro dissolution profile of EFA in pure form and SD in capsule

 

Figure 6:  Overlain IR spectrums of (a) pure EFA and (b) EFA SD4

 

DSC study:

DSC study is performed to identify the state of the system²¹. The DSC thermogram for EFA alone and its SDs are shown in Fig.7. The DSC thermograms of pure EFA shows sharp endothermic peak at 137.44ºC attributed to the melting of EFA. This sharp melting peak indicates the crystalline nature of drug. The DSC thermogram of SD shows absence of characteristic melting endotherm of EFA as well as change in the heat capacity around 57ºC attributed to the single glass transition temperature (T_g) of SD indicating the perfect miscibility of drug and polymer. As single T_g is characteristic of the thermoplastic system, the DSC thermogram of SD shows complete amorphization of EFA.

 

 

 

PXRD study:

The existence of crystallinity is indicated by the presence of sharp peaks in the diffractogram of a material²². The XRD patterns are shown in Fig. 7. The diffractogram of pure EFA showed numerous distinct peaks indicating presence of high crystalline state. The XRD pattern of SD of sample SD4 exhibited diminishing effect on the intensity of majority characteristic diffraction peaks of EFA. These observations revealed that the crystallinity was reduced to a greater extent in the SD. PXRD profiles of the SD4 also lacked some of the diffraction peaks associated with EFA implying the amorphous nature of EFA. The existence of EFA in an amorphous form could be one of the mechanisms responsible for improved dissolution.

 

 

Figure 7: DSC thermograms of pure EFA and its solid dispersion (SD4)

 

Figure 8: X- ray diffraction patterns of pure EFA and EFA SD.

 

 

CONCLUSION:

Preliminary solubility analysis of EFA SD helped in selection of carriers. Formulating EFA as SD using PEG and PS enhanced solubility and improved dissolution rate. The amorphization improved solubility of EFA as confirmed by PXRD and DSC studies. EFA when formulated with PEG enhanced dissolution rate.

 

ACKNOWLEDGEMENT:

The authors are thankful to Emcure Pharmaceuticals Pune for providing drug to carry out the research work.

 

REFERENCES:

1.       Leuner C and Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur. J.Pharm.50; 2000: 47–60.

2.       Kalyanwat R and PatelS.Solid Dispersion: A Method for Enhancing Drug Dissolution. Int. J. Drug Forml. Res. 1(3); 2010: 1-14.

3.       Chiou WL and Riegelman S. Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci. 60(9); 1971: 1281-1302.

4.       Costa P and Lobo JMS. Modeling and comparison of dissolution profiles. Eur. J.Pharm. Sci.13; 2001: 123-133.

5.       Dhirendra K, et al., Solid Dispersions: A Review. Pak. J. Pharm. Sci. 22(2); 2009: 234-246.

6.       Vadnere MK. Coprecipitates and melts. In Encyclopedia of pharmaceutical technology edited by Swarbrick J and Boylan JC. New York, USA: Marcel Dekker, Inc. 2002; 2nd ed: pp. 641-647.

7.       Betageri GV and Makarla KR. Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques. Int. J. Pharm.126; 1995:155-160.

8.       Patro S and Choudhary AA. Effect of some hydrophilic polymers on dissolution rate of roxithromycin. Indian J. Pharm. Sci.67; 2005: 334-341.

9.       Serajuddin ATM, et al., Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems and recent breakthroughs. J. Pharm. Sci. 88; 1999: 1058–1066.

10.     Akiladevi D, et al., Preparation and evaluation of paracetamol by solid dispersion technique. Int. J. Pharm. Pharm. Sci. 3(1); 2011: 188-191.

11.     Averineni RK, et al., Enhanced dissolution and bioavailability of gliclazide using solid dispersion techniques. Int. J. Drug Deliv. 2; 2010: 49-57.

12.     Zaki Aand Abdel-Raheem I. Solubility enhancement of meloxicam prepared via binary and ternary phases using spray congealing. Asian J. Pharm. Health Sci. 1(4); 2011: 196-203.

13.     Timko RJ and Lordi NG. Thermal analysis studies of glass dispersion systems. Drug Dev. Ind. Pharm.10(3); 1984:  425-451.

14.     Damian F, et al., Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30. Int. J. Pharm. 244(1-2); 2002: 87-98.

15.     Vippagunta SR, et al., Solid-state characterization of nifedipine solid dispersions. Int. J. Pharm. 236(1-2); 2002: 111-123.

16.     Save T and Venkitachalam P. Studies on solid dispersions of nifedipine. Drug Dev. Ind. Pharm. 18(15); 1992: 1663-1679.

17.     McGinity JW, Maincent P and Steinfink H. Crystallinity and dissolution rate of tolbutamide solid dispersions prepared by the melt method. J. Pharm. Sci. 73(10); 1984: 1441-1444.

18.     Morris KR, Knipp GT and Serajuddin ATM. Structural properties of poly (ethylene glycol)- polysorbate 80 mixture, a solid dispersion vehicle. J. Pharm. Sci. 81; 1992: 1185-1188.

19.     Serajuddin ATM, et al., Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly- water soluble drug from solid dispersions. J. Pharm. Sci.77; 1988: 414-417.

20.     Appa Rao B. et al., Formulation and evaluation of aceclofenac solid dispersions for dissolution rate enhancement. Int. J. Pharm. Sci. Drug Res. 2(2); 2010: 146-150.

21.     Hajare AA, More HN and D’souza JI. Design and Evaluation of sustained release tablets of Diltiazem Hydrochloride., Indian Drugs. 41(3); 2004: 176.

 

 

Received on 23.06.2012       Modified on 16.07.2012

Accepted on 25.12.2012      © RJPT All right reserved

 

22.     Patil PB, Hajare AA and Awale RP. Development and Evaluation of Mesalamine Tablet Formulation for Colon Delivery. Res. J. Pharm. and Tech. 4(11):Nov. 2011.