studies on release of hydrophilic drugs from gelucire

STUDIES ON RELEASE OF HYDROPHILIC DRUGS FROM GELUCIRE MATRIX :

STUDIES ON RELEASE OF HYDROPHILIC DRUGS FROM GELUCIRE MATRIX MASTER OF PHARMACY Degree In PHARMACUETICS By Varsha Deva B. Pharm. Prof. Anurag Verma M.Pharm . (Ph.D.) SUPERVISOR College of Pharmacy Institute of Foreign Trade and Management, Moradabad (U.P .). GAUTAM BUDHA TECHNICAL UNIVERSITY, LUCKNOW, INDIA Formerly, Uttar Pradesh Technical University, Lucknow , India 2010

Abstract:

Abstract The aim of present investigation was to study the effect of two drugs having similar solubility profile on their release from Gelucire 39/01 matrices. Matrices of different ratios of Gelucire with Metoprolol Succinate and Diphenhydramine Hydrochloride were prepared separately by melt solidification technique and studied using Differential Scanning Calorimetry (DSC), hot stage polarized microscopy (HSPM) and dissolution. Incorporation of metoprolol succinate in progressive concentrations into Gelucire 39/01 resulted in progressive decrease in total heat of fusion with the exception of formulation V2 and V4 where it was increased. On the other hand incorporation of progressive concentration of diphenhydramine hydrochloride resulted in mixed and different thermal behaviour. Overall, it was observed that incorporation of metoprolol succinate resulted in decrease in high melting point fraction, whereas, incorporation of diphenhydramine resulted in increase of high melting fraction. HSPM studies also indicated that metoprolol succinate appeared to act as nucleation site for the lower melting fraction, whereas, diphenhydramine hydrochloride appeared to act as nucleation site for higher melting fraction. Dissolution studies at 37 ºC showed that metoprolol succinate to be released at a relatively faster rate than diphenhydramine hydrochloride. From the results obtained, it is suggested that influence of drug should be carefully considered when studying Gelucire matrix systems.

INTRODUCTION:

INTRODUCTION Development of oral controlled/sustained delivery systems for stomach specific delivery is not an easy job. Because not only physicochemical properties of drug(s) but also polymer(s) along with gastrointestinal constraints have to be studied. To overcome gastrointestinal constraints is not a major problem as a number of technologies have been developed to deal with this problem. Polymers plays a central role in the fabrication of sustained/controlled release system and in fact it is one of the enduring features for current drug delivery technologies. Polymers from natural, semi-synthetic, synthetic and biotechnological origin have been extensively investigated. Recently, lipids have gained attention as an alternative to polymers due to their advantages like the potential biocompatibility and biodegradability, low melting viscosity and the absence of toxic impurities such as residual monomer catalsty and initiators. One of those lipids is “ Gelucire ” which comprising blends of:- pure glycerides like mono-, di -and triglycerides of saturated fatty acids, mixtures of glycerides and fatty acid esters of polyethylene glycols like mono-and di -fatty acid esters in various proportions, pure poly ethylene glycol (PEG) esters with no glycerides present as in the case of G 55/18.

Slide 4:

Gelucires are inert materials derived from natural hydrogenated food-grad oils and fats Synthesized by an alcoholysis reaction whereby coconut, palm or palm kernel oil is hydrolysed and the fatty acids removed by fractional distillation. These fatty acids are then esterified with PEG at 230 o C under a nitrogen atmosphere. Besides alcoholysis , it can also be manufactured by the direct esterification of fatty acids with glycerol and PEG. Gelucires are excipients with amphiphilic character. The amphiphilicity of the base attributed to the long hydrocarbon chain and the alcohol moieties that make these bases suitable as a lipid carrier for both hydrophilic and lipophilic drugs . They are identified with respect to their melting point and HLB value. In the designation of gelucire names, for example, Gelucire 39/01, 39 indicates melting point (melting range) and 01 indicates its HLB value.

Slide 5:

The first no. is nominal melting point only be used as a reference and does not represent the accurate melting point of the base. The second number which represents the HLB value extends from 0 to approx 20. Pharmaceutical Applications: Dissolution and Bioavailability enhancers Sustained-release formulations

Slide 6:

Method for Analysis of Gelucire Containing Formulations The physical stability of drug in the matrix systems as a function of time, temperature and relative humidity can be studied. Differential scanning calorimetry (DSC) & powder X-ray diffractometry (PXRD): crystallinity and polymorphic and/or pseudo-polymorphic form of drug in a matrix containing Gelucire can be studied. Diffuse Reflectance Infrared Fourier transform spectroscopy (DRIFTS): The nature of the interactions between drug and the constituents of the polymeric matrix Hot Stage Microscopy (Thermo microscopy) Hot Stage Polarizing Microscopy (HSPM) Saturation solubility of formulation. Scanning Electron Microscopy (SEM)

Slide 7:

Objective In the current investigation we will carry out the series of study that focus on solid state characterization (thermal analysis and microscopy) and drug release studies (dissolution and drug release investigation) in order to elucidate, how the solid state structure may vary between drug systems and may in turn influence product performance. For this two model drugs namely “ Diphenhydramine Hydrochloride and Metaprolol Succinate ” were selected due to the similarity in the solubility in water. But have different molecular weight. These two drugs was incorporated separately in Gelucire 39/01 which is our model gelucire in this study. Gelucire 39/01 is inert, waxy and having low HLB value i.e. 1 which suggests its lipophilic character. It has a nominal melting point of 39°C.

METHODOLOGY:

METHODOLOGY Preparation of Gelucire -drug dispersion Gelucire 39/01 and both the drugs were accurately weighed and then both the drugs seprately added to molten gelucire with continuous stirring at 40-45 o C for about 10 mins . S . No. Formulation Amount Of Polymer ( Gelucire 39/01 ) (in mg) Amount of Metoprolol succinate (in mg) 1. V1 1500 100 2. V2 1000 100 3. V3 500 100 4. V4 500 200 5. V5 500 250 6. V6 500 500 S. No. Formulation Amount Of Polymer ( Gelucire 39/01 ) (in mg) Amount of Diphenhydramine Hydrochloride (in mg) 1. F1 1500 100 2. F2 1000 100 3. F3 500 100 4. F4 500 200 5. F5 500 250 6. F6 500 500

:

Evaluation DSC Studies Heating rate of 2 o C /min was used with the purge gas nitogen at relatively low rate in order to maximise peak resolution. Hot Stage Microscopy About 2mg of ample is placed on a glass slide and then covered with coverslip . Then these slides examined uder optical microscope having hoty stage.the sample is heated at the rate of 2 o C/min from room temperasture to 50 o C where it is hold for 30 mins and ten cooled upto 25 o C. Further at this temperature hold for 30 min and reheating is done. In Vitro Dissolution Studies Dissolution studies were carried out using USP type II dissolution apparatus.dissolution is done at 100 rpm at 37 o C temperature. 0.1N Hcl used as dissolution medium.

RESULT AND DISCUSSION:

RESULT AND DISCUSSION DSC Studies A total of six dispersions were prepared with increasing order of drug concentration. All the six dispersions were subjected to DSC studies and thermograms are depicted. Table of heat of fusion of Gelucire and Metoprolol Succinate dispersion Gelucire 39/01 : Drug Ratio DSC Code New Formulation code Drug Concentration % Drug release in 8 hours Heat of Fusion (J/g) LMF Heat of Fusion (J/g) HMF Total Heat of Fusion (J/g) 0:0 ----- ----- 0% ------ 64.03 12.28 76.31 15:1 FC V1 6.6% 71.24 51.53 4.23 55.76 10:1 FB V2 9.09% 92.67 65.06 5.5 70.57 5:1 FA V3 16.66% 45.43 46.04 3.51 49.55 2.5:1 FD V4 28% 89.27 69.59 5.7 75.29 2:1 FE V5 33% 89.47 35.61 8.54 44.15 1:1 FF V6 50% 99.02 38.38 2.07 40.45

Slide 11:

Table of heat of fusion of gelucire and diphenhydramine dispersions Gelucire :Drug Ratio DSC Code New formulation code Drug Concentration % Drug released in 8 hours Heat of Fusion (J/g) LMF Heat of Fusion (J/g) HMF Total Heat of Fusion (J/g) 0:0 ----- ----- 0% ----- 64.03 12.28 76.31 15:1 F3 F1 6.6% 65.97 64.06 13.09 77.15 10:1 F2 F2 9.09% 82.41 81.52 6.06 87.58 5:1 F1 F3 16.66% 42.39 37.88 8.35 46.23 2.5:1 F4 F4 28% 82.2 35.48 11.09 46.57 2:1 F5 F5 33% 43.01 65.86 14.46 80.32 1:1 F6 F6 50% 89.11 33.72 4.17 37.89

DSC Curves Sample blank(gelucire only):

DSC Curves Sample blank( gelucire only) The thermogram showed two endothermic peaks at 34.48 ○ C and 42.86 ○ C. The total heat of fusion of Gelucire 39/01 alone was 76.31 J/g. The thermogram clearly indicated that Gelucire 39/01 exist in two crystalline forms with low melting fraction (LMF) gave first endothermic peak (heat of fusion= 64.03 J/g) and high melting fraction, the second endothermic peak (heat of fusion= 12.28 J/g).

The melting peak of metoprolol succinate was not considered to be reliable indicator of miscibility due to the possibility of sublimation, degradation of the Gelucire at the elevated temperature involved and drug dissolution in the molten lipid, hence, focus of the study was on the melting behaviour of Gelucire 39/01. Sample V1 :

The melting peak of metoprolol succinate was not considered to be reliable indicator of miscibility due to the possibility of sublimation, degradation of the Gelucire at the elevated temperature involved and drug dissolution in the molten lipid, hence, focus of the study was on the melting behaviour of Gelucire 39/01. Sample V1

Sample V2:

Sample V2

Sample V3:

Sample V3

Sample V4:

Sample V4

Sample V5:

Sample V5

Sample V6:

Sample V6 With the exception of mixes V2 and V4, the total heat of fusion decreased compared to pure Gelucire 39/01 (Table 3) which would be expected for non-interacting systems. Decrease in heat of fusion of both LMF and HMF was observed .However, decrease in higher melting fraction was comparatively higher. In case of mixes V2 and V4, increase in total heat of fusion compared to other mixes could be attributed to the increase in material in LMF.

Sample F1:

Sample F1 Addition of Diphenhydramine to the Gelucire 39/01 resulted in altogether different melting profile than metoprolol succinate containing mixes.

Sample F2:

Sample F2

Sample F3:

Sample F3

Sample F4:

Sample F4

Sample F5:

Sample F5

Sample F6:

Sample F6

Slide 25:

Mixes F1, F2 and F3, addition of diphenhydramine hydrochloride resulted in increase in total heat of fusion. Here increase in both LMF and HMF was observed with the exception of F2 where there was decrease in HMF, compared to gelucire 39/01 . In formulation F2, addition of diphenhydramine resulted in increased heat of fusion of LMF which suggest that most of the incorporated material remained in LMF. On the other hand, mixes F3, F4 and F5 showed progressive decrease in heat of fusion of LMF. The above findings suggest that the choice of drug may have a profound effect on the solid state profiles that may be ascribed to polymorphic transformation in case of both drugs at particular drug: Gelucire ratio.

Slide 26:

Hot Stage Polarized Microscopic Studies The hot stage polarized microscopy studies suggested that at first on heating Gelucire 39/01 alone melted over a wide temperature range, as indicated by the DSC studies, although precise onsets were difficult to ascertain due to non-homogeneity of changes in the physical state seen across the field of view. A more clear differentiation between structures was possible on cooling. At 39 ○ C, Gelucire 39/01 seemed to be almost completely melted with some small spherical particles of HMF. Upon further heating melted Gelucire begins to flow with formation of some bigger spherical structures. Upon cooling and holding at 25 ○ C for 30 min it was observed that Gelucire 39/01 solidifies showing scattered spherically congealed compact particles. Upon reheating (Fig. 5.6) these particles slowly begins to melt again at almost the same temperature. Metoprolol containing mixes (V1) which clearly showed drug ( which was amorphous when added) in crystalline form, evidence of some crystal growth were also observed. Reheating photographs of mix V2 shows accumulation of drug crystals which were surrounded by spherical particles of HMF.

Slide 27:

Photographs of HSPM

Slide 30:

Sample V1

Slide 34:

Sample V2

Slide 38:

Sample V5

Slide 40:

Heating photographs of mix V5 shows bed of drug crystals which seems to be bonded together and upon continuously increasing temperature there structure could not disturbed. Further, oil streak material was also observed.

Slide 43:

On the addition of diphenhydramine hydrochloride, the profile observed on first heating was similar to that seen from DSC thermogram of Gelucire 39/01 , indicating that drug did not induce any morphological changes prior to fusion as in the case of mix F1. Heating photographs (Fig. 5.12) showed the presence of the drug in the form of crystals surrounded by HMF of Gelucire as the heating continues the HMF begins to melt and at 45 ○ C the fraction was completely disappeared.

Slide 47:

Photographs of mix F2 (heating) shows melting of Gelucire which then surrounded the drug crystals as oil streak material. The photographs also showed instances of crystal growth. The cooling photographs shows formation of new phase as congealed particles at 25 ○ C.

Slide 48:

Sample F3

Slide 52:

The cooling photographs of mix F3 at 25 ○ C showed extensive spherical crystals of Gelucire 39/01 which upon reheating gradually disappears at 38 ○ C. This study has indicated that the presence of incorporated drugs may have a profound effect on the structure and behaviour of Gelucire 39/01 . DSC and HSPM studies indicated that the metoprolol succinate in fact partially dissolved in the molten liquid and then recrystallised . On the other hand diphenhydramine is, however, clearly altering the structure of Gelucire base. The presence of diphenhydramine hydrochloride increased the proportion of material in both LMF and HMF at particular concentrations. It is recognized that triglycerides crystallizes into distinct forms, commonly assigned α. β and β’ corresponding to a metastable hexagonal form that is seen on rapid cooling of the lipid, a triclinic and an orthorhombic form of the lipid, respectively. It is well recognized that generation of various polymorphic forms may be strongly influenced by the presence of nucleating agents. It is reasonable to suggest that both the drugs at particular drug: Gelucire ratio act as a nucleating agent for LMF and HMF.

In Vitro Dissolution Studies:

In Vitro Dissolution Studies Initial inspection of data showed that, in case of metoprolol succinate the rate of drug release depended upon the Gelucire : drug ratio. As drug concentration was increased in the mixes, the rate of drug release (during the first hour). However, in case of formulation V3 and V5, which contained 16.66 and 33.33% drug concentration respectively, there was decrease in the rate of drug release during the first hour, but at the end of eightth hour the difference was insignificant, which could be attributed to the erosion of Gelucire . Whereas, in case of mix V3 the difference was significant. This change in drug release could be attributed to the polymorphic transformation in Gelucire 39/01 matrix which resulted in decrease in LMF and increase in HMF (in case of mix V5, which is evident from the table, which showed increase in heat of fusion of HMF. In case formulation V3, the delay in release could be attributed to the decrease in LMF along with crystal growth in metoprolol succinate .

Slide 54:

% Drug release ( Metoprolol Succinate ). Time in hrs. V1 V2 V3 V4 V5 V6 1 1.09 5.11 3.69 10.14 2.08 18 2 4.33 12.35 8.02 19.21 7.9 32.07 3 13.69 36.22 16.91 32.18 16.92 50.67 4 37.01 44.17 19.17 47.37 29.1 68.99 5 42.2 50.13 23.62 54.21 40.18 82.5 6 57.68 72.27 30.31 71.97 55.29 89.6 7 66.71 83.44 39.06 81.21 72.58 94.19 8 71.24 92.67 45.43 89.27 89.47 99.02

Slide 55:

In case of diphenhydramine , initial inspection of drug release data indicates a low rate dependence on initial drug loading. In case of formulation F1, F2, F4 and F6, the increase in drug concentration resulted in increase in drug release at the end of eightth hour; however, there was no significant difference in the first hour drug release. Mixes F3 and F5 showed significant retardation in drug release. This could be related to the findings from DSC studies, which showed considerable increase in the heat of fusion of HMF in both mixes. The increase in HMF might have resulted in delayed release of drug from mixes F3 and F5.

% Drug release (Diphenhydramine Hydrocloride):

% Drug release ( Diphenhydramine Hydrocloride ) Time in hrs. F1 F2 F3 F4 F5 F6 1 4.95 8.53 2.31 6.94 7.34 6.61 2 15.6 16.11 8.18 17.77 12.07 14.71 3 28.91 23.74 13.01 39.21 15.63 20.18 4 30.5 32.94 19.63 43.6 18 34.99 5 52.63 54.72 22.45 57.28 21.55 42.69 6 56.71 62.01 28.39 66.67 26.19 59.45 7 62.33 76.33 34.51 73.79 38.14 68.37 8 65.97 82.41 42.39 82.2 43.01 89.11

Release Kinetics:

Release Kinetics Formulation New Code Zero Order First Order Higuchi Korsemeyer model n Value V1 0.96 0.8819 0.8115 0.9728 2.125 V2 0.9828 0.8251 0.8655 0.975 1.423 V3 0.9855 0.8583 0.865 0.9894 1.192 V4 0.9948 0.7626 0.9016 0.9955 1.082 V5 0.9578 0.9147 0.7777 0.9986 1.805 V6 0.9555 0.6445 0.9544 0.9812 0.8587 Formulation New Code Zero Order First Order Higuchi Korsemeyer model n Value F3 0.9904 0.8672 0.8684 0.9856 1.335 F2 0.9828 0.8089 0.8595 0.9852 1.146 F1 0.9695 0.7893 0.8943 0.9697 1.246 F4 0.9843 0.7612 0.9174 0.973 1.186 F5 0.9618 0.7717 0.8629 0.9536 0.815 F6 0.9742 0.8439 0.8264 0.9906 1.243 Table for showing release kinetics of both the drugs from G elucire matrix Diphenhydramine Hydrochloride Metoprolol Succinate

Release Kinetics:

Release Kinetics In case of metoprolol succinate drug release data fitted predominantly to Korsemeyer model (V1, V3, V4, V5 and V6) as indicated by r 2 values. Mix V2 well fitted to zero order model (r 2 =0.9855). Korsemeyer model indicate combined effect of difusion and erosion mechanism for drug release. The values of n ranged from 0.86 to 2.12. It was observed that as the concentration of drug matrix increased the value of n decreased with the exception of mix V5, where it was increased. From the n values, it was suggested that with the exception of mix V6 all other mixes followed super case II transport mechanism. Whereas, the mix V6 followed non- Fickian anomalous diffusion. In case of diphenhydramine hydrochloride containing mixes, it was observed that both zero order (F3, F4 and F5) and Korsmeyer models (F1, F2 and F6) were followed as evidenced by r 2 values. This behavior indicated that the drug release from the mixes is independent of concentration of drug in the Gelucire matrix. The n values ranged from 0.81 to 1.33. With majority (F1, F2, F3, F4 and F6) of mixes following super case II transport mechanism of drug release, whereas, mix F5 followed anomalous non- Fickian diffusion.

CONCLUSION:

CONCLUSION The study has indicated that the choice of drug may have a profound effect on the structure and Metoprolol Succinate and Diphenhydramine Hydrochloride showed markedly different solid state profile that may be ascribed as polymorphic transformations. Overall the study suggests that the effect of drug incorporation on both the matrix, and the drug itself should be considered when formulating drug dispersion in lipid matrices. THAT’S ALL……..Thank You.

References:

References A.B. Dennis, S.J. Farr, I.W. Kellaway , G. Taylor, R. Davidson, In vivo evaluation of rapid release and sustained release gelucire capsule formulations, Int. J. Pharm. 65 (1990) 85– 100. D.Q.M. Craig, The use of glycerides as controlled releasematrices , in: D.R. Karsa , R.A. Stephenson (Eds.), Excipients and Delivery Systems for Pharmaceutical Formulations, Royal Society of Chemistry, Cambridge, 1995, pp. 148– 174. N. Passerini , B. Perissutti , M. Moneghini , D. Voinovich, B. Albertini , C. Cavallari , and L. Rodriguez. Characterization of carbamazepine-gelucire 50/13 microparticles prepared by a spray-congealing process using ultrasounds. J. Pharm. Sci. 91 699-707. S.A. Barker, S.P. Yap, K.H. Yuen, C.P. McCoy, J.R. Murphy,D.Q.M . Craig, An investigation into the structure and bioavailability of a- tocopherol dispersions in Gelucire 44/14, J. Control. Release 91 (2003) 477– 488. T.H. Applewhite in Bailey’s industrial Oil and Fat Products, vol. 3. John Wiley and Sons, New York, 1985, pp. 203– 214, 273–319. W. Sutananta , D.Q.M. Craig, J.M. Newton, An evaluation of the mechanisms of drug release from glyceride bases, J. Pharm. Pharmacol . 47 (1995) 182– 187. W. Sutananta , D.Q.M. Craig, J.M. Newton, An investigationi nto the effect of preparation conditions on the structure and mechanical properties of pharmaceutical glyceride bases, Int.J . Pharm. 110 (1994) 75– 91. W. Sutananta , D.Q.M. Craig, J.M. Newton, The effects of ageing on the thermal behaviour and mechanical properties of pharmaceutical glycerides , Int. J. Pharm. 111 (1994) 51– 62.