OPTIMIZATION OF CLASS II BCS DRUG USING SOLID DISPERSION TECHNIQUE

Transcription

1 Academic Sciences International Journal of Pharmacy and Pharmaceutical Sciences ISSN Vol 4, Suppl 5, 2012 OPTIMIZATION OF CLASS II BCS DRUG USING SOLID DISPERSION TECHNIQUE Research Article ABSTRACT M.A. EL-NABARAWI 1, 2,*, M.F. EL-MILIGI 1, 2, I.A. KHALIL 2 1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt, 2 Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Misr University for Science and Technology, Cairo, Egypt. islamkhll@yahoo.com Received: 06 Oct, 2012, Revised and Accepted: 07 Nov, 2012 The aim of this study was to develop Aceclofenac solid dispersion (ACSD) formulation using different types of carriers. Aceclofenac is class II BCS (High permeability, Low solubility). This solid dispersion should Have many properties. Firstly, it should have high solubility and dissolution not less than 85% after 5 minutes in simulated saliva fluid (SSF) (ph 6.8 medium). Secondly, it should have high solubility and dissolution not less than 85% after 30 minutes in simulated gastric fluid SGF (ph 1.2 medium). Finally, all these properties should achieve the acceptable level of drug content and process yield (85-115%). By achieving these properties, it will give the ability to formulate Aceclofenac fast disintegrating tablet beside immediate release tablet with high drug dissolution. This study was conducted on two phases (screening phase and optimization phase).in screening phase, different types of carriers were used to prepare binary solid dispersion at different levels. In optimization phase, Polymer carriers were selected as primary carrier due to meeting target attribute. Precipitation inhibitor and ph modifier were selected as optimizer carriers. One factor at a time (OFAT) experimental design was applied to develop space design and determine the control space of ACSDs that have optimum solubility and dissolution. The prepared solid dispersions with drug were characterized for drug content, process yield, a solubility study and invitro drug dissolution study in SSF ph (6.8) and SGF ph (1.2). Also, a physicochemical characterization (differential scanning calorimetry, Fourier transform Infra-Red and Powder X-ray diffraction) of AC and its SD were done. There was no interaction between AC and additives physical mixtures were observed according to differential scanning calorimetry (DSC) thermograms and Infra-Red (IR) spectrums. The crystal structure of AC was reformed to partially or amorphous form by the additives in SD. In screening phase, Binary solid dispersion (BSD) containing polymer and surfactant gave higher solubility and faster dissolution rate when compared to corresponding pure drug. While, ph modifier BSD were enhanced solubility and initial dissolution rate followed by returning to the original drug profile. This may attributed to drug precipitation after a period of time. In optimization phase, Ternary solid dispersion (TSD) containing precipitation inhibitor enhanced solubility and dissolution rate. Also, TSD containing ph modifier enhanced solubility and only initial dissolution rate when compared to its BSD.QSD had highest solubility and dissolution rate due to increase wettability, amorphous formation, control microenvironment ph of solid dispersion and prevent precipitation of AC in QSD. Therefore, preparation of Aceclofenac QSD was optimized AC properties that suitable for different type of tablets in a different ph. Keywords: Aceclofenac, Solid Dispersion, Carrier, Solubility, Dissolution INTRODUCTION The Biopharmaceutics Classification System (BCS)is a scientific framework for classifying a drug substance based on its aqueous solubility, dose, and intestinal permeability. The BCS guidance is generally considered to be conservative with respect to the class boundaries of solubility, permeability, and the dissolution criteria. Thus, the possibility of modification of these boundaries and criteria has received increasing attention 1,2. In general, The poor absorption of BCS Class II drugs can be overcome with various formulation technologies like Particle size reduction, Salt formation, Precipitation inhibitors, Metastable forms, Solid dispersion, Complexation and Lipid Technologies 3. Aceclofenac (BCS Class II drug) is an orally effective non-steroidal antiinflammatory drug (NSAID)which possesses remarkable analgesic, antipyretic and anti-inflammation in osteoarthritis and rheumatoid arthritis. Itis a weakly acidic drug (pka= 4 5), practically insoluble in water and acidic ph conditions, but slightly solubility in basic ph conditions. There are certain problems coming with using Aceclofenac as traditional oral tablet which includes bioavailability of Aceclofenac is highly variable due to its low aqueous solubility and first pass metabolism. Also, common NSAIDs side effects. In order to improve the solubility, dissolution rate and bioavailability of the drug, it was attempted to prepare optimized Aceclofenac solid dispersion. Hence, many water insoluble drugs have low dissolution rates due to their crystalline structures. Solid dispersions (SDs) are one of effective techniques for enhancing dissolution rate via structural alterations of crystalline drugs into amorphous forms 4. However, the solubilization capacity of SD systems is inadequate in many cases, resulting in recrystallization or precipitation in a spring-like manner upon exposure to an aqueous solution. Therefore, pharmaceutical strategies require more detailed dissolution controlling mechanisms of SDs. Several solid dispersion system were prepared for the enhancement of solubility, dissolution rate, absorption rate and hence bioavailability of Aceclofenac. for example SD with PEG , PVP 6,9 11, PVP/VA , Mannitol 6,11 14, Lactose 12,13, Urea 6,11 16, sodium citrate 15,16, Aeglemarmelos gum 17, β-cyclodextrin 7, Poloxamer 407 4,8, Avicel , Sylysia , SLS 10,19, APG 19, Gelucire 44/14 4, Cremophor RH40 4 and sodium carbonate 4 Different strategies were used to improve the effect of solid dispersion. Precipitation inhibitor and polymers can be simultaneously combined and incorporated in SD systems for the complete solubilization of poorly water soluble drugs by limiting spring like precipitation in solution. Incorporation of ph modifiers is a common strategy to enhance the dissolution rate of weakly acidic or basic drugsif the solubility of the drug is dependent on ph 4, These ph modifiers can alter the microenvironmental ph within and surrounding a dissolving solid to an optimal ph for controlled solubility The microenvironmental ph can be defined as the ph of the saturated solution in the immediate vicinity of the drug particles and has been used to modify the dissolution of ionizable drugs from pharmaceutical formulations in a predictable manner 20. The aim of this study was to prepare Aceclofenac solid dispersion by screening different type of excipients. This approach could in turn greatly aid in the selection of a suitable excipient for formulating as a solid dispersion to practically realize the solubility advantage of amorphous pharmaceutical. Different pharmaceutical excipients were tested like polymer, surfactant, hydrotrope, polyols and ph modifier.the most promising excipients were selected and optimized using dissolution controlling mechanisms of ph modifier and/or precipitation inhibitor systems. Different ph modifiers were tested. The higher effect on Aceclofenac solubility was selected. The prepared solid dispersions with drug were characterized for drug content, process yield, a solubility study and in-vitro drug dissolution study in SSF ph (6.8) and SGF ph (1.2). Also,a physicochemical characterization (differential scanning calorimetry, Fourier transform Infra-Red and Powder X-ray diffraction) of AC and its SD were investigated.

2 [ Nabarawi et al. MATERIALS AND METHODS Materials Polyethylene glycols PEG 4000 and PEG 8000 (Fluka, Switzerland), Polyvinyl pyrrolidones PVP K30 and PVP K90(BDH Chemicals Ltd. Poole, England), Hydroxypropyl methylcellulose (HPMC) E5; (Colorcon, Kent, U.K.), Inutec SP1 (Orafti Bio Based Chemicals, Belgium), Gelucire 44/14, (Gatteffosse, France), Mannitol, Sorbitol, Sodium Acetate, Sodium Benzoate, Sodium Citrate, Sodium Salicylate, Urea, Methanol, Disodium hydrogen phosphate, and potassium dihydrogen phosphate and hydrochloric acid (El-Nasr company, Egypt). Solubility studies of Aceclofenac (AC) In 30 ml screw-capped vials,aknown excess amount of AC was added to 10 ml of the medium. The vials were shaken (200 rpm)for 48 hours in an incubator shaker (Incubator Shaker; Lab-Line, USA) at 37± 0.5 o C. The solution was filtered using 0.45 µm Millipore filter and properly diluted. The concentration of the drug was measured spectrophotometrically (UV/VIS spectrophotometer, DU 640; Beckman, California, USA) at the predetermined λmax of Aceclofenac. All experiments were run in triplicates manner 20,21.The medium used in this study was deionized water, simulated saliva fluid without enzymes ph=6.8(ssf), simulated gastric fluid without enzymesph=1.2 (SGF) and 1% (w/v) ph modifier in deionized water [sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), calcium carbonate (CaCO3), disodium hydrogen phosphate(na2hpo4) and dipotassium hydrogen phosphate (K2HPO4)].In addition, this study was carried out to determine the saturated solubility of the prepared ACSDs in SSF and SGF and to select a suitable dissolution medium for the in vitro dissolution studies. Formulation of optimized Aceclofenac solid dispersions (ACSD) In screening phase, ACSDs were prepared using different types of carriers. Binary solid dispersions (BSD) were prepared as shown in table 1. In optimization phase, three Polymer carriers (PVP K30, PEG 4000 and HPMC E5) were selected as primary carrier at Drug to polymer ration (1:1). Precipitation inhibitor and ph modifier were selected as optimizer carriers. They were selected to increase wettability and control microenvironment ph of solid dispersion respectively. OFAT experimental design was applied by preparing Ternary solid dispersions (TSD) were prepared by adding precipitation inhibitor or ph modifier to study the effect of each carrier alone as shown in table 1. While, quaternary solid dispersions (QSD) were prepared by adding surfactant and ph modifier to prepare the optimum formulation 20. Preparation of Aceclofenac solid dispersions (ACSD) Gelucire and polyols based ACSD was prepared using the hot melting method in an oil bath. Aceclofenac was incorporated in the molten carrier at 60 o C. The mixture was stirred continuously for 15 min until a homogenous mixture was obtained On the other hand, the other ACSDs were prepared by solvent evaporation method. Each carrier was dissolved in a suitable solvent using magnetic stirrer (Fisher thermix stirring hot plate, Model 210T, USA) at room temperature. When a clear solution was obtained drug was dispersed in the solution until a uniform mixture was obtained. The solution was evaporated under vacuum at 45 O C (Vacuum rotary evaporator; Buche, Switzerland). All solid dispersions were subsequently desiccated under vacuum for 48 hours and sieved (USA standard testing sieve set) through a sieve (size 60) and retained on a sieve (size 80) 27,28. Further evaluation, three batches of solid dispersion were prepared. Table 1: composition of different type of Aceclofenac solid dispersions Type Carriers Type Carrier 1 Carrier 2 Carrier 3 Ratios (D:C1:C2:C3) Screening Phase BSD P* PEG 4000, PEG 8000, PVP K30, PVP K90, (1:1) (1:2) (1:4) HPMC E5 SAA** Inutec SP1, (2:1) (1:1) (1:2) Gelucire 44/14 Hydrotropic agent Sodium Acetate, Sodium Benzoate, (1:1) (1:2) (1:4) Sodium Citrate, Sodium Salicylate, Urea Polyols Mannitol, Sorbitol (1:1) (1:2) (1:4) phm*** Sodium Carbonate (2:1) (1:1) (1:2) Optimization phase TSD P* : PPTI*** PEG 4000, PVP K30, HPMC E5 Inutec SP1 (1:1:0.5) (1:1:1) P* : phm**** PEG 4000, PVP K30, HPMC E5 Sodium (1:1:0.5) (1:1:1) Carbonate PPTI*** : phm**** Inutec SP1 Sodium Carbonate (1:1:0.5) (1:1:1) QSD P* : PPTI*** : phm**** PEG 4000, PVP K30, HPMC E5 Inutec SP1 Sodium Carbonate (1:1:1:0.5) (1:1:1:1) * P = polymer; ** SAA = surfactant; *** PPTI = precipitation inhibitor; ****phm = ph modifier Percent practical yield (PY%) The importance of percentage practical yield was the selection of appropriate method of manufacturing. The practical yield (PY) was determined after collecting and weighing of ACSDs by the following equation 12,13 : PY%= Practicalsoliddipsersionweight Theoretical Drug+Carrier weight 100 Equation (1): Percent practical yield Percent drug content (DC%) An amount of ACSD, equivalent to 100 mg of Aceclofenac, was dissolved in a 100 ml volumetric flask containing suitable solvent. After dissolving the contents, appropriate filtration, dilution was done and drug content was analyzed spectrophotometrically 12,13. The actual drug content was determined using the following equation: In- vitro dissolution study DC%= Practicaldrugcontent Theoreticaldrugcontent 100 Equation (2): Percent drug content The dissolution profiles of the pure drug and its solid dispersions were determined using USP apparatus II (Dr. Schleuniger Pharmaton, type Dissolution 6000, Switzerland)paddle method [50 rpm, 37±1 o C, and 300 ml of SS For in 900 ml SGF with 2% tween ]. The solid dispersion equivalent to 100 mg AC was accurately weighed (Electric balance; Sartorius, Goettingen, Germany). Three milliliters samples were withdrawn, and replaced at predetermined intervals 5, 10, 15, 30, 60, 90 and 120minutes. Samples were filtered using 0.45 µm Millipore filter and properly diluted. The concentration of the drug was measured spectrophotometrically at the predetermined λmax of Aceclofenac for SSF and SGF. All experiments were run in triplicates

3 A cumulative correction factor was made for the previously removed samples to determine the total amount released according to the following equation 32,33 : 1 Cn=Cnmeas+A/V Csmeas =1 Equation (3): Cumulative correction factor Characterization of dissolution profile using model independent approach Different parameters were used for characterizing drug dissolution curve which were area under the dissolution curve (AUC), area between the drug dissolution curve and its asymptote (ABC), mean residence time of the drug substance molecules in the dosage form (MRT), mean dissolution time (MDT), variance of dissolution time (VDT), moments of dissolution times of order k (mk), percent drug dissolved(%q)and percent dissolution efficiency (%DE). All these parameters were calculated according to equations mention in Brockmeieret al, Voegele et aland Pinto et al and The release rate constant (Kd) 37. Comparison of dissolution profile using fit factors A mathematical approach for calculating Similarity factor (f2) and dissimilarity factor (f1) was used for comparison among the dissolution profiles which proposed by Costa, P. and Sousa Lobo, J.M. 38. The f2 and f1 is a measure of similarity and dissimilarity factor respectively, between two dissolution profiles and is given by equation 7 and 8 respectively 7,18,39. Equation (4): Dissimilarity factor 40 Equation (5): Similarity factor 40 Where n is the number of withdrawal points, Rj is the percentage dissolved of reference at the time point t, and Tj is the percentage dissolved of test at the time point t.a value of 100 for f2 suggests that test and reference profiles are identical. Values between 50 and 100 indicate that the dissolution profiles are similar, whereas smaller values imply increase in dissimilarity. The difference factor (dissimilarity factor f1) measures the percent error between the two profiles over all time points. The value of f1 is zero when the test and drug reference profiles are identical and increase proportionally with the dissimilarity between the two dissolution profiles 18. Measurement of ph in solubility media and dissolution media After the solubility study and the dissolution study, the ph of the solutions were measured using ph meter using a ph meter (Hanna, type 211, Romania) 20,21. Differential scanning calorimetry (DSC) Samples (3-4 mg) were placed in an aluminum pan and heated at a rate of 10 C/min, with indium in the reference pan, in an atmosphere of nitrogen to a temperature of 350 o C. The DSC (Differential scanning calorimeter DSC-50; Shimadzu, Kyoto, Japan)studies were performed for the drug, the carriers and the drug solid dispersions 7,18. Powder X- ray diffraction (PXRD) Samples of pure drug, carriers and drug solid dispersions were irradiated with monochromatized CuKα radiation (X-ray diffraction; Scintag Inc., USA), (40kV x 30mA) at a scan rate 8 o / min. from 4.00 o C to o C. The output is given as intensity versus 2θ 19. Fourier-transform infrared spectroscopy (FTIR) A FTIR spectrophotometer (FT-IR spectrophotometer; Bruker 22, UK) was used for drug, carriers and solid dispersions. FTIR spectrum measured using the KBr disc technique in the range of 4000 to 500 cm -1 with 2 cm -1 resolution 13,18. Scanning electron microscopy Shape and surface morphology characterization of Aceclofenac, QSD formulations was performed by scanning electron microscopy (SEM, LEO SUPRA 55, Carl Zeiss, Germany) measured at the working distance around12 mm and an accelerated voltage of 20kV with SE2 type. SEM was used under high vacuum 70mTorr and high voltage of 30mV. Statistical analysis Comparison was performed using one-way ANOVA (analysis of variance). Post-hoc statistical analyses were performed using Tukey- Karmer test for multiple comparisons. The software employed was Graph Pad Instat V2.04 and level of significance was set at 5%. RESULTS AND DISCUSSIONS Solubility studies of AC in different media Aceclofenac is an ionizable weakly acidic drug with pka= 4 5. So, Aceclofenac is practically insolubility in acidic medium and slightly soluble in basic medium. In table 2, the solubility of AC around 60 µg/ml in deionized water but in SGF ph 1.2 it was 10 µg/ml. on the other hand, the solubility of AC in SSF ph 6.8 was around 6500 µg/ml. these results were matched with those of previous report 31, and could be attributed to the deprotonating of AC in a basic ph, subsequently forming a soluble compound 4.This proves that AC solubility is ph dependent. Incorporating of ph modifier in deionized water was increase ph of the medium. Subsequently, it increased AC solubility 4. Na2CO3showed the highest ph value and highest solubility which was 80481µg/ml. Therefore, Na2CO3was selected as a model ph modifier for the preparation of ACSD. Several methods studied the selection of proper dissolution medium, the use of media having surfactants was recommended as a proper method for solubilizing such drugs, because various surfactants are existing in the gastrointestinal fluid, e.g., bile salts, lecithin, cholesterol and its esters 41. Tween 80 has been successively used to develop dissolution media for poorly watersoluble drugs 42. AC showed satisfactory solubility in SGF +2% Tween 80 which was suitable to maintain sink condition. So, it was selected as the dissolution medium. Pharmaceutical evaluation of different type of Aceclofenac SD Aceclofenac BSD (Screening phase) The drug content was determined in the BSDs. It was found to be 85.33% 108.5% with a practical yield 72.3% 98.3% for a three batches of solid dispersion. The results of saturated solubility study present in table 3.In SSF, all polymer carriers, Inutec SP1 and Na2CO3 showed a significant increase in solubility than pure drug. They converted to soluble or slightly soluble class. Most of other carriers showed a significant increase at a ratio (1:4) and became slightly soluble. All BSDs and AC belong to BCS class I in basic medium. The ph of the medium after solubility study was around 6.8 for all Aceclofenac BSD except Na2CO3 was above 8.In SGF, All Aceclofenac BSD showed a significant increase in AC solubility except sodium acetate and sodium salicylate in (1:1) ratio. The ph of the medium after solubility study was around 1.2 for all Aceclofenac BSD except Na2CO3 was above6. The dissolution profile parameters of BSD are shown in table 4 for SSF and in table 5 for SGF. The dissolution profile of the pure AC was determined in SSF and SGF with 2% tween 80. The release of AC, a weakly acidic drug, was 65% at ph 6.8, but was 40%at ph 1.2 after 2 hours. In both media, The AC profile showed low value of AUC, Kd, %Q and %DE, beside high value of ABC, MRT, MDT, VDT and mk. The target dissolution profile in both media was high value of AUC, Kd, %DE5 (in SSF), %DE30 (in SGF) and %DE120(in both media), with low value of ABC, MRT, MDT, VDT and mk. Fit factors were adopted by FDA Center for Drug Evaluation and Research (CDER) and the 556

4 similarity factor was also adopted by the European Medicines Evaluation Agency (EMEA) Committee for Proprietary Medicinal Products (CPMP) as an assessment criterion of similarity between two in-vitro dissolution profiles 40. By increasing f1 and decreasing f2the dissimilarity to pure drug profile will increase. All Aceclofenac BSD presented dissimilarity to AC profile except hydrotropic agent and polyols in low ratio. Polymer carriers and Na2CO3 revealed highest dissimilarity to AC profile in both media. The ph of SSF medium after dissolution study was around (6.8). While, SGF medium after dissolution study was around (1.2). Table 2: solubility of Aceclofenac in different media Media Solubility of AC (µg/ml) ph after solubility study Deionized water ± 0.06 SGF ph= ± ± 0.13 SSF ph= ± ± % (w/v) NaHCO3 in deionized water ± ± 0.2 1% (w/v) Na2CO3 in deionized water ± ± 0.2 1% (w/v) CaCO3 in deionized water ± ± % (w/v) Na2HPO4 in deionized water ± ± % (w/v) K2HPO4 in deionized water ± ± 0.24 SGF ph= % Tween ± 1.24 SGF ph= % Tween ± 2.45 SGF ph= % Tween ± 3.95 SGF ph= % Tween ± 4.84 SGF ph= % Tween ± 4.55 SGF ph= % Tween ± 5.15 SGF ph= % Tween ± 6.45 AceclofenacBSD (polymer carriers) In solubility and dissolution studies, all levels of polymer carriers showed significant increase than pure drug in SGF and SSF. The rank order of solubility in both media and dissolution parameters in SGF were PEG 4000 > PEG 8000 > PVP K30 > PVP K90 > HPMC. On the other hand, dissolution parameters in SSF were PVP K30 > PVP K90 > PEG 4000 > PEG 8000 > HPMC. MDT value is used to describe drug release rate and indicates the drug release enhancing efficiency of polymer 43. The MDT value was found to be a function of polymer loading. A lower MDT indicates a higher drug enhancing ability of the polymer and vice versa.de is used as criterions for comparing the effect of polymer concentration on the release. It is applied to check the solubility enhancement of drug in the presence of other substances. High DE value indicates higher solubilization and vice versa so, the dissolution profile with lowest MDT and highest DE could be selected as best BSD. PEG 4000 based BSD was converted AC to a soluble form. MDT, DE and other parameters of PEG 4000 based BSD was confirmed the fulfillment of the objective for dissolution enhancement of Aceclofenac. The fact that the intimate mixing of drug and carrier is at molecular degree during manufacturing step, provides more wetting of drug molecules with the dissolution medium and improved dissolution 44. PEGs have been extensively used as carriers for solid dispersions due to their favorable solution properties, low melting point, rapid solidification rates, low toxicity and low cost 45. PEGs of molecular weight are the most frequently used for the production of solid dispersions, because in this molecular weight range the water solubility is very high, but hygroscope is not a problem and the melting points are already over 50 C.these results was also matched with those of a previous reports They were proved advantage of PEG among other carriers except Aejaz et al 6. He found urea gave better results than PEG. PVPs showed two opposite attribute in different media. For example, they presented lowest MDT and highest DE in SSF and came after PEGs in SGF. The chain length of the PVP has a very significant impact on the dissolution rate of the dispersed drug from the solid dispersion. The aqueous solubility of the PVPs becomes poorer and viscosity higher with increasing chain length. So, PVP K30 showed better profile than PVP K90. PEGs and PVPs have good water solubility and can convert drug to amorphous form which increase the wettability of the dispersed compound in many cases. This was matched with those of a previous reports HPMC is one cellulose polymers which are naturally occurring polysaccharides that are ubiquitous in the plant kingdom. Many drugs were exhibit faster release from solid dispersion in HPMC include the poorly soluble weak acids nilvadipine 51, benidipine 52, Carbamezapine 53, docetaxel 54 and cisapride 55. In this study, HPMC based BSD presented the lowest solubility and dissolution profile among other polymer BSD. On the other hand, it showed better attribute among other type of BSD. These results made polymer BSD a good candidate for further optimization of AC properties. It was observed that increasing polymer ratio presented higher solubility and dissolution profile like 1:4 drug to polymer ratio. On the other hand, the equivalent amount of AC dose (100 mg) will be high (500 mg). So, drug to polymer ratio 1:1 appeared to be optimal with regard to technical feasibility for tablet process. AceclofenacBSD (surfactant carriers) The release behavior of many drugs can be improved by using of emulsifying agents. Two mechanisms are possible, which are improvement of wetting characteristics and solubilization of the drug 56. Gelucire 44/14 and other grades is recently used surfactant carrier. The grades of Gelucire are denoted by different number like 44/14, in that first digit denotes the melting point of carrier and second digit denotes HLB value of carrier. Enhanced dissolution was observed with Rofecoxib 57, UC , Piroxicam 30, α-tocopherol 29, Aceclofenac 4, Tiaprofenic acid 58 and Thiocarboxanilide UC when Gelucire 44/14 is used as surfactant alone and with other carriers. Inutec SP1 is a derivative of inulin. It contains a hydrophilic inulin back bone to which lipophilic alkyl side chains are covalently linked. Inutec SP1 has polymer and surfactant properties due to the presence of both hydrophilic and lipophilic parts of the molecule 59,60. Inutec SP1 used as a carrier for SDs of diazepam, fenofibrate, ritonavir, and efavirenz 59, Itraconazole 61,felodipine 62, Carvedilol 63, Etodolac 64 and docetaxel 54. Other advantages of Inutec SP1 are a low viscosity and preservation of its stabilizing effect on emulsions and suspensions with high electrolyte concentrations 61,65. In SSF, Inutec SP1 based BSD showed significant increase of AC solubility while Gelucire 44/14 showed no significant difference. On the other hand, both of them showed significant increase in solubility in SGF with advantage of Inutec SP1 based BSD. The dissolution profile of both surfactants BSD showed dissimilarity profile to pure drug in both media. In SSF, Inutec SP1 based BSD showed better results in AUC, ABC, MRT, MDT, Kd, DE30 and DE120 than Gelucire 44/14 based BSD. On the other hand, All Gelucire 557

5 44/14 based BSD showed better results DE5. In addition, Gelucire 44/14(2:1) ratio presented better ABC, MDT and Kd. Similar results were observed in SGF without advantage of(2:1) ratio of Gelucire 44/14.These results made Inutec SP1 based BSD a good candidate for further optimization of AC properties. Aceclofenac BSD (hydrotropic agent carriers) In SSF, Most hydrotropic agents and polyols showed a significant effect only in high drug to polymer ratio. This could be explained by the fact that the hydrotropic solubilization phenomenon is occurring when large amount of hydrotropic agent present in water. All hydrotropic agents showed significant increase of AC solubility except Sodium Salicylate (1:1) ratio in SGF. In dissolution study, most hydrotropic agent showed approximately the same dissolution parameters in both media. Urea is the end product of human protein metabolism, has a light diuretic effect and is regarded as non-toxic. Its solubility in water is greater than 1 in 1 and it also exhibits good solubility in many common organic solvents. Despite that, Urea based BSD showed the lowest dissolution parameters in SGF and one of the lowest BSD in SGF. This was in agreement with a previous report 11,13,14,66, But in contrary with Aejaz et al. 6. He reported that the release rate from urea dispersions was faster than from other studied carriers, including PEG 6000, PVP and Mannitol. Aceclofenac BSD (polyols carriers) Sugars and related compounds are highly water soluble but some sugars are toxic. They are facing problems than other carriers for the production of solid dispersions. The high melting point of most sugars making it difficult to prepare by the hot melt method, and poor solubility in most organic solvents is making preparation by solvent evaporation method problematic. Despite these disadvantages, several efforts to prepare solid dispersions using sugars and their derivatives have been reported 56. Mannitol, which has a melting point of C and decomposes only above 250 C, can be employed in some cases to prepare dispersions by the hot melt method.also, Improved release profiles have been reported for sorbitol dispersions of several compounds, including nitrofurantoin 67, Ketoprofen 50, Aceclofenac 49,prednisolone 68, and ofloxacin 69. In most of these cases, other carriers produced better results. Remarkably, nitrofurantoin showed better release from sorbitol than Mannitol dispersions. In contrary, a dispersion of prednisolone in sorbitol released the drug faster than PEG, PVP, urea and Mannitol 70.In this study, a significant increase in AC solubility was observed just for (1:4) ratio in SSF. On the other hand, all ratios showed significant increase in solubility in SGF. Dissimilarity to dissolution profile of pure drug was observed at (1:4) ratioonly in both media. Aceclofenac BSD (ph modifier carrier) Na2CO3 showed highest solubility of AC in both media. This might be attributable to ph modulation 20.In dissolution study; the fit factors indicated dissimilarity to pure dug. Na2CO3 based BSD showed the greatest potential in increasing AC release rates. However, the enhanced dissolution rapidly decreased due to spring like precipitation of AC. this was observed in dissolution parameters (high ABC, MDT, Kd, DE5 and DE30 and low MRT and DE120).For this reason, incorporation of Na2CO3 with polymer or surfactant will be a good approach to prevent spring like precipitation of AC 4. Aceclofenac TSD and QSD (Optimization phase) In general, the carrier to drug ratio was control drug dissolution rates and crystallinity of SD. Increasing carrier ratio in SD was converted into amorphous form leading to increase dissolution rate of drug. This effect was observed in Aceclofenac BSD for SSF and SGF. The enhancing effect of carrier was maximized to a certain limit at high drug to carrier ratio. Dissolution enhancement of BSD by itself was insufficient. Addition of more carriers could be not efficient and would rather inhibit initial release. SAA was used as precipitation inhibitor and increase wettability. To optimize these dissolution profiles, TSDs were prepared by incorporation either surfactant or ph modifier. Further optimization was achieved by preparing QSD. In the optimization phase; TSDs and QSDs were compared with its BSD properties not with the pure drug using fit factors. The drug content was determined in the TSDs and QSDs. It was found to be 86.27% 105.1% with a practical yield 71.4% 91.2% for a three batches. Aceclofenac TSD by incorporation surfactant Ina previous studies; they investigated the potential enhancement of dissolution by surfactant with other carriers in SDs with hydrophobic drugs, for example mefenemic acid 72, Carvedilol 63 and oxazepam 73. In the present study; the results of solubility study was shown in table 6. All TSD using Inutec SP1 were significantly increase AC solubility in both media. Increasing Inutec SP1 ratio was enhanced drug solubility in all polymers. However; the solubility of these TSDs was not showed any significant enhancement than its BSD. The dissolution curves presented different patterns. In SSF; Inutec SP1 showed significant increase in the initial dissolution of AC. however; this enhancement was stopped after around 1 hour and the dissolution curve returned to its original profile of BSDs. the dissolution parameters proved these findings by high %DE5 and %DE30. Also, there was slight enhancement in AUC, ABC, MRT and MDT. The fit factors showed a dissimilarity of PEG 4000 TSDs and HPMC TSDs. on the other hand, it showed some similarity in case of PVP K30 TSDs when they compared with their original BSDs. Table 8 showed the dissolution profiles of TSDs in SGF. The fit factors showed some similarity between TSDs and their BSDs. this could return to the following; as the solubility of AC in dissolution media was highly increased, the saturation concentration in the boundary layer around the SD particles will also be increased. Therefore, the driving forces for drug dissolution will be increased to the maximum limit, after that limit there is a risk of drug recrystallization 59. Aceclofenac TSD by incorporation ph modifier The incorporation of ph modifier in TSD showed great impact on drug solubility in both media as shown in table 6. This could be explained by the fact that ph modifier was modulate the ph of AC. Table 7 presented the dissolution profiles in SSF. Na2CO3showed the same effect that presented in BSD, which was initial increase then rapidly decrease in dissolution profile. On the other hand, the time decreasing effect was limited due to the presence of primary carrier except in Inutec SP1 based TSDs. HPMC based TSDs showed the least reduction in dissolution but the overall dissolution still the lowest profile. These finding was proved by observing %DE of TSDs and their BSD as shown in table 7.The fit factors verified the dissimilarity between TSDs and their BSDs. Table 8 showed the dissolution profiles of TSDs in SGF. All observations of SSF were presented in SGF profiles as shown in table 8. This could be explained by spring like precipitation behavior was still present but the presence of another carrier was decrease the rate of precipitation of AC 4. Aceclofenac QSD by incorporation surfactant and ph modifier As shown in table 6; the solubility of AC was significantly enhanced in both media. The dissolution profile was also enhanced and optimized as presented in table (7-8) and figure (1-2). The incorporation of precipitation inhibitor and ph modifier together in the same polymer SD showed enhanced initial dissolution profile with a verylimited decreasing in dissolution curves, which mean prevent spring like drug precipitation 4,20,22.So, QSD had highest solubility and dissolution rate due toincrease wettability, control microenvironment ph of solid dispersion and prevent precipitation of AC in QSD. PEG 4000 and PVP K30 based QSDs at ratio (1:1:1:1) achieved the target of this study in optimizing AC properties in SSF and SGF. This target could not achieved by BSDs even at high drug to polymer ratio. Therefore, preparation of Aceclofenac QSD was optimized AC properties that suitable for different type of tablets in a different ph. 558

6 Table 3: Saturated solubility study of Aceclofenac BSD with ph of different media F#***** SSF ph 6.8 SGF ph 1.2 AC (mg/ml) ph q* Sign** Solubility class*** BCS class**** AC (mg/ml) ph q* Sign** Solubility class*** BCS class**** Aceclofenac 6.57 ± Sl. Sol. I 0.01 ± Pr. Insol. II PEG 4000 (1:1) ± S Sp. Sol I 1.33 ± S Sl. Sol. I (1:2) ± S Sol I 1.94 ± S Sl. Sol. I (1:4) ± S Sol I 2.53 ± S Sl. Sol. I PEG 8000 (1:1) ± S Sp. Sol I 0.41 ± S V. Sl. Sol. I (1:2) ± S Sp. Sol I 0.76 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 1.76 ± S Sl. Sol. I PVP K30 (1:1) ± S Sp. Sol I 0.92 ± S V. Sl. Sol. I (1:2) ± S Sp. Sol I 0.95 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 1.09 ± S Sl. Sol. I PVP K90 (1:1) ± S Sp. Sol I 0.26 ± S V. Sl. Sol. I (1:2) ± S Sp. Sol I 0.35 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.43 ± S V. Sl. Sol. I HPMC E5 (1:1) ± S Sp. Sol I 0.55 ± S V. Sl. Sol. I (1:2) ± S Sp. Sol I 0.64 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.65 ± S V. Sl. Sol. I Inutec SP1 (2:1) ± S Sp. Sol I 0.67 ± S V. Sl. Sol. I (1:1) ± S Sp. Sol I 0.72 ± S V. Sl. Sol. I (1:2) ± S Sp. Sol I 0.76 ± S V. Sl. Sol. I Gelucire 44/14 (2:1) 7.18 ± N S Sl. Sol. I 0.47 ± S V. Sl. Sol. I (1:1) 7.35 ± N S Sl. Sol. I 0.67 ± S V. Sl. Sol. I (1:2) 9.38 ± N S Sl. Sol. I 0.70 ± S V. Sl. Sol. I Sodium Acetate (1:1) 7.03 ± N S Sl. Sol. I 0.17 ± N S V. Sl. Sol. II (1:2) 8.39 ± N S Sl. Sol. I 0.47 ± S V. Sl. Sol. I (1:4) 9.86 ± N S Sl. Sol. I 0.56 ± S V. Sl. Sol. I Sodium Benzoate (1:1) 7.50 ± N S Sl. Sol. I 0.38 ± S V. Sl. Sol. II (1:2) 7.66 ± N S Sl. Sol. I 0.45 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.59 ± S V. Sl. Sol. I Sodium Citrate (1:1) 6.92 ± N S Sl. Sol. I 0.23 ± S V. Sl. Sol. II (1:2) 7.27 ± N S Sl. Sol. I 0.41 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.45 ± S V. Sl. Sol. I Sodium Salicylate (1:1) 9.13 ± N S Sl. Sol. I 0.17 ± N S V. Sl. Sol. II (1:2) ± S Sp. Sol I 0.40 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.42 ± S V. Sl. Sol. I Urea (1:1) 9.33 ± N S Sl. Sol. I 0.26 ± S V. Sl. Sol. II (1:2) 9.47 ± N S Sl. Sol. I 0.58 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.61 ± S V. Sl. Sol. I Mannitol (1:1) 6.94 ± N S Sl. Sol. I 0.10 ± S V. Sl. Sol. II (1:2) 9.39 ± N S Sl. Sol. I 0.41 ± S V. Sl. Sol. I (1:4) ± S Sp. Sol I 0.45 ± S V. Sl. Sol. I Sorbitol (1:1) 8.59 ± N S Sl. Sol. I 0.28 ± S V. Sl. Sol. II (1:2) 9.85 ± N S Sl. Sol. I 0.30 ± S V. Sl. Sol. II (1:4) ± S Sp. Sol I 0.42 ± S V. Sl. Sol. I Sodium Carbonate (2:1) ± S Sol I 5.15 ± S Sl. Sol. I (1:1) ± S Sol I 5.63 ± S Sl. Sol. I (1:2) ± S Sol I 6.83 ± S Sl. Sol. I * If the value of q is greater than then the P value is less than 0.05 (Significantly different); ** Significance (S = significantly different and NS = Non significantly different); *** Solubility Class (Sol = soluble, Sp. Sol. = sparingly soluble, Sl. Sol. = slightly soluble, V. Sl. Sol. = very slightly soluble and Pract. Insol. = practically insoluble); **** BCS class 71 (if the highest dose that is soluble in 250mL or less = Class I, if soluble in more = Class II); ***** In a solid dispersion ratio, the first number in the ratio is assigned for pure Aceclofenac 559

7 Table 4: parameters of dissolution profile of Aceclofenac BSD in SSF F#* AUC ABC MRT MDT Kd VDT mk %Q5 %Q30 %Q120 %DE5 %DE30 %DE120 f1 f2 ph AC PEG 4000 (1:1) PEG 4000 (1:2) PEG 4000 (1:4) PEG 8000 (1:1) PEG 8000 (1:2) PEG 8000 (1:4) PVP K30 (1:1) PVP K30 (1:2) PVP K30 (1:4) PVP K90 (1:1) PVP K90 (1:2) PVP K90 (1:4) HPMC (1:1) HPMC (1:2) HPMC (1:4) Inutec (2:1) Inutec (1:1) Inutec (1:2) Gelucire (2:1) Gelucire (1:1) Gelucire (1:2) Sod. Acetate (1:1) Sod. Acetate (1:2) Sod. Acetate (1:4) Sod. Benzoate (1:1) Sod. Benzoate (1:2) Sod. Benzoate (1:4) Sod. Citrate (1:1) Sod. Citrate (1:2) Sod. Citrate (1:4) Sod. Salicylate (1:1) Sod. Salicylate (1:2) Sod. Salicylate (1:4) Urea (1:1) Urea (1:2) Urea (1:4) Mannitol (1:1) Mannitol (1:2) Mannitol (1:4) Sorbitol (1:1) Sorbitol (1:2) Sorbitol (1:4) Sodium Carbonate (2:1) Sodium Carbonate (1:1) Sodium Carbonate (1:2) Target value high low low low high low low high high high high high high high low * In a solid dispersion ratio, the first number in the ratio is assigned for pure Aceclofenac 560

8 Table 5: parameters of dissolution profile of Aceclofenac BSD in SGF F#* AUC ABC MRT MDT Kd VDT mk %Q5 %Q30 %Q120 %DE5 %DE30 %DE120 f1 f2 ph AC PEG 4000 (1:1) PEG 4000 (1:2) PEG 4000 (1:4) PEG 8000 (1:1) PEG 8000 (1:2) PEG 8000 (1:4) PVP K30 (1:1) PVP K30 (1:2) PVP K30 (1:4) PVP K90 (1:1) PVP K90 (1:2) PVP K90 (1:4) HPMC (1:1) HPMC (1:2) HPMC (1:4) Inutec (2:1) Inutec (1:1) Inutec (1:2) Gelucire (2:1) Gelucire (1:1) Gelucire (1:2) Sod. Acetate (1:1) Sod. Acetate (1:2) Sod. Acetate (1:4) Sod. Benzoate (1:1) Sod. Benzoate (1:2) Sod. Benzoate (1:4) Sod. Citrate (1:1) Sod. Citrate (1:2) Sod. Citrate (1:4) Sod. Salicylate (1:1) Sod. Salicylate (1:2) Sod. Salicylate (1:4) Urea (1:1) Urea (1:2) Urea (1:4) Mannitol (1:1) Mannitol (1:2) Mannitol (1:4) Sorbitol (1:1) Sorbitol (1:2) Sorbitol (1:4) Sodium Carbonate (2:1) Sodium Carbonate (1:1) Sodium Carbonate (1:2) Target value high low low low high low low high high high high high high high low * In a solid dispersion ratio, the first number in the ratio is assigned for pure Aceclofenac 561

9 Table 6: saturated solubility study of Aceclofenac TSD and QSD with ph of different media F#***** SSF ph 6.8 SGF ph 1.2 AC (mg/ml) ph q* Sign ** Solubility class*** BCS class**** AC (mg/ml) ph q* Sign ** Solubility class*** BCS class**** Aceclofenac 6.57 ± Sl. Sol. I 0.01 ± Pr. Insol. II PEG 4000 : Inutec SP1 (1:1:0.5) ± S Sp. Sol I 1.68 ± S Sl. Sol. I PEG 4000 : Inutec SP1 (1:1:1) ± S Sp. Sol I 2.14 ± S Sl. Sol. I PEG 4000 : Sod Carbonate (1:1:0.5) ± S Sol I 7.45 ± S Sl. Sol. I PEG 4000 : Sod Carbonate (1:1:1) ± S Sol I 8.24 ± S Sl. Sol. I PEG 4000 : Inutec SP1: Sod Carb (1:1:1:0.5) ± S Sol I 6.99 ± S Sl. Sol. I PEG 4000 : Inutec SP1: Sod Carb (1:1:1:1) ± S Sol I 8.31 ± S Sl. Sol. I PVP K30 : Inutec SP1 (1:1:0.5) ± S Sp. Sol I 0.56 ± S V. Sl. Sol. I PVP K30 Inutec SP1 (1:1:1) ± S Sp. Sol I 1.05 ± S Sl. Sol. I PVP K30 : Sod Carbonate (1:1:0.5) ± S Sol I 6.55 ± S Sl. Sol. I PVP K30 : Sod Carbonate (1:1:1) ± S Sol I 7.12 ± S Sl. Sol. I PVP K30 : Inutec SP1: Sod Carb (1:1:1:0.5) ± S Sol I 6.30 ± S Sl. Sol. I PVP K30 : Inutec SP1: Sod Carb (1:1:1:1) ± S Sol I 7.85 ± S Sl. Sol. I HPMC : Inutec SP1 (1:1:0.5) ± S Sp. Sol I 0.67 ± S V. Sl. Sol. I HPMC Inutec SP1 (1:1:1) ± S Sp. Sol I 0.68 ± S V. Sl. Sol. I HPMC : Sod Carbonate (1:1:0.5) ± S Sol I 5.95 ± S Sl. Sol. I HPMC : Sod Carbonate (1:1:1) ± S Sol I 6.74 ± S Sl. Sol. I HPMC : Inutec SP1: Sod Carb (1:1:1:0.5) ± S Sol I 5.55 ± S Sl. Sol. I HPMC : Inutec SP1: Sod Carb (1:1:1:1) ± S Sol I 6.68 ± S Sl. Sol. I Inutec : Sod Carbonate (1:1:0.5) ± S Sol I 5.65 ± S Sl. Sol. I Inutec : Sod Carbonate (1:1:1) ± S Sol I 6.47 ± S Sl. Sol. I * If the value of q is greater than then the P value is less than 0.05 (Significantly different); ** Significance (S = significantly different and NS = Non significantly different); *** Solubility Class (Sol = soluble, Sp. Sol. = sparingly soluble, Sl. Sol. = slightly soluble, V. Sl. Sol. = very slightly soluble and Pract. Insol. = practically insoluble); **** BCS class 71 (if the highest dose that is soluble in 250mL or less = Class I, if soluble in more = Class II); ***** In a solid dispersion ratio, the first number in the ratio is assigned for pure Aceclofenac Table 7: parameters of dissolution profile of Aceclofenac TSD and QSD in SSF F#* AUC ABC MRT MDT Kd VDT mk %Q5 %Q30 %Q120 %DE5 %DE30 %DE120 f1 f2 ph AC PEG 4000 : Inutec SP1 (1:1:0.5) PEG 4000 : Inutec SP1 (1:1:1) PEG 4000 : Sod Carbonate (1:1:0.5) PEG 4000 : Sod Carbonate (1:1:1) PEG 4000 : Inutec SP1: Sod Carb (1:1:1:0.5) PEG 4000 : Inutec SP1: Sod Carb (1:1:1:1) PVP K30 : Inutec SP1 (1:1:0.5) PVP K30 Inutec SP1 (1:1:1) PVP K30 : Sod Carbonate (1:1:0.5) PVP K30 : Sod Carbonate (1:1:1) PVP K30 : Inutec SP1: Sod Carb (1:1:1:0.5) PVP K30 : Inutec SP1: Sod Carb (1:1:1:1) HPMC : Inutec SP1 (1:1:0.5) HPMC Inutec SP1 (1:1:1) HPMC : Sod Carbonate (1:1:0.5) HPMC : Sod Carbonate (1:1:1) HPMC : Inutec SP1: Sod Carb (1:1:1:0.5) HPMC : Inutec SP1: Sod Carb (1:1:1:1) Inutec : Sod Carbonate (1:1:0.5) Inutec : Sod Carbonate (1:1:1) * In a solid dispersion ratio, the first number in the ratio is assigned for pure Aceclofenac 562

10 F#* AUC ABC AC PEG 4000 : Inutec SP1 (1:1:0.5) PEG 4000 : Inutec SP1 (1:1:1) PEG 4000 : Sod Carbonate (1:1:0.5) PEG 4000 : Sod Carbonate (1:1:1) PEG 4000 : Inutec SP1: Sod Carb (1:1:1:0.5) PEG 4000 : Inutec SP1: Sod Carb (1:1:1:1) PVP K30 : Inutec SP1 (1:1:0.5) PVP K30 Inutec SP1 (1:1:1) PVP K30 : Sod Carbonate (1:1:0.5) PVP K30 : Sod Carbonate (1:1:1) PVP K30 : Inutec SP1: Sod Carb (1:1:1:0.5) PVP K30 : Inutec SP1: Sod Carb (1:1:1:1) HPMC : Inutec SP1 (1:1:0.5) HPMC Inutec SP1 (1:1:1) HPMC : Sod Carbonate (1:1:0.5) HPMC : Sod Carbonate (1:1:1) HPMC : Inutec SP1: Sod Carb (1:1:1:0.5) HPMC : Inutec SP1: Sod Carb (1:1:1:1) Inutec : Sod Carbonate (1:1:0.5) Inutec : Sod Carbonate (1:1:1) * In a solid dispersion ratio,, the first number in the ratio is assigned for pure Aceclofenac Nabarawi et al. Table 8: parameters of dissolution profile of Aceclofenac TSD and QSD in SGF MRT MDT Kd VDT mk %Q5 %Q30 %Q120 %DE %DE30 %DE120 f1 f2 ph Fig. 1: dissolution profile of AC-QSD in SSF 563

11 Fig. 2: dissolution profile of AC-QSD in SGF Physicochemical evaluation of different type of Aceclofenac SD Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) is a famous technique that measures heat flow into or out of a material as a function of time or temperature. Crystallinity can be determined with DSC by quantifying the heat associated with melting (fusion) of the material.dsc thermograms of pure AC, physical mixture (PM) with carriers, BSD, TSD and QSD are shown in figure (3). Pure AC was highly crystalline compound exhibited a single sharp endothermic peaks at 153ºCcorresponding to the melting point of the drug. PEG 4000 exhibited a single endothermic peak at 58ºC. PVP K30 and HPM Cexhibited a single broad endothermic peak at 103ºC and 63ºC, respectively. These peaks were corresponded to their intrinsic melting points.na2co3 did not show any peak due to its high melting point. Inutec SP1 is characterized by a small endothermic peak at 68ºC with a glass transition at 103.2ºC. This glass transition is covered due to the large water evaporation endotherm. It has been shown that inulin is a semi-crystalline oligosaccharide and the small endothermic peak can probably be attributed to a crystalline fraction of Inutec SP1.Melting of AC could be observed in all physical mixtures as the characteristic peak of the drug in its place with slightly shifts or decrease in intensity. Therefore, AC was remained in the crystalline state. In DSC curves of PEG 4000 based SDs; PEG 4000 showed a melting endotherm peak at 58 C. The characteristic melting point peak of PEG 4000 existed in all the cases, but varied via its molecular interaction with other components. In BSD and TSD with Inutec SP1, the peak of AC was decreased in intensity with slight shift in position. On the other hand; TSD with Na2CO3 and QSD showed disappearance of AC peak. These were suggesting the transformation of the drug from its crystalline form into the semiat 103 Cdue to water crystalline or amorphous one. PVP K30 showed a melting endotherm peak removal at about 64 to 128 C. This suggestion, which was substantiated by findings that enthalpies of vaporization are close to the value for water, is adopted to explain the present observations. Melting of AC in PVP K30 based SDs could not be observed which suggesting the amorphous form. The sharp melting point peak of pure AC appeared at 153ºC, whereas no such peak was observed in solid dispersions prepared with HPMC except BSD, suggesting that AC was molecularly dispersed and in an amorphous form. However, in the case of BSD, a small AC melting point peak was observed, suggesting that some crystalline AC still remained. Inutec SP1 based BSD showed a small AC peak. On the other hand; TSD of Inutec SP1 with Na2CO3 made AC peak disappear. From all DSC curves; the enhanced AC dissolution rate seemed to result from this transformation of drug s crystalline structure. However, these DSC thermograms could not completely explain the differences in drug dissolution. Powder X- ray diffraction (PXRD) Powder X-ray diffraction as a consequence of the importance of solid drug substance characterization, analytical tools such as X-ray diffractometry are usually employed in the pharmaceutical field. PXRD diffractograms of pure drug, carriers and various SD systems were investigated in figure(4). The incorporation of different carriers with AC showed a great impact on AC characteristic peaks. The diffraction pattern of pure AC was highly crystalline in nature as indicated by numerous peaks. Several peaks at 8.75, 11.5, 16.75, 17.5, 18, 18.5, 19.5, 21.75, 22, 24, 26, 26.5, 32, 33 and 37.5 were noticeable and the main peak at 26 was particularly distinctive. It is known that the lack of a distinctive peak of a drug in SD systems reveals thata high concentration of the drug is dissolved in the solid state 74. Moreover, a large reduction in characteristic peaks indicates anamorphousstate 75. Basedon the diffractograms of SDs, The results of the PXRD patterns were quite different from that of DSC thermograms of the BSDs. The characteristic peaks of AC were disappeared in PXRD. In contrary, AC peaks decrease in DSC thermograms of BSD except PVP and disappear in DSC thermograms of TSD and QSD except PEG 4000: Inutec SP1. The disappearance of drug peaks was indicating an amorphous state. Crystallinity fewer than 2% generally cannot be detected with DSC 76, which may explain why the DSC thermograms of drug existing in a partially amorphous form did not exhibit a characteristic peak. The PXRD pattern of PEG 4000 had three characteristic peaks of high intensity at 15, 19.2 and Nevertheless; the spectrum of PVP K30, HPMC E5, Inutec SP1 and their SD were characterized by the complete absence of any diffraction peak which is characteristic of an amorphous compound. The characteristic peaks of PEG 4000 existed in all SD with decreased in of peaks intensity. TSDs and QSDs incorporating Na2CO3 showed that AC existed in a totally amorphous pattern. Also; most peaks disappeared when Inutec SP1 were incorporated in TSDs and QSDs. Furthermore, these PXRD diffractograms clearly elucidated the roles of the Inutec SP1 in changing the drug s crystalline structure into an almost totally amorphous form, improving the drug dissolution rate without showing spring like precipitation of the drug. 564

12 Fig. 3: DSC thermograms of pure Aceclofenac, physical mixture (PM) with carriers, BSD, TSD and QSD Fig. 4: XRD diffractogram of pure Aceclofenac, BSD, TSD and QSD 565

13 Fourier-transform infrared spectroscopy (FTIR) Pure Aceclofenac FTIR spectra measured to investigate the molecular interactions among functional groups. Structural changes and the lack of a crystal structure can lead to changes in the molecular bonding energy between functional groups which can be detected by FTIR spectroscopy 76.The FTIR spectrum of pure Aceclofenac and that of the physical mixtures and optimum solid dispersions are shown in figures(5 7). The spectrum of Aceclofenac showed characteristic bands at cm 1 (N H stretching), and cm 1 (O H stretching), & cm -l of C=O (carbonyl group of ester) stretching vibration, cm 1 (skeleton vibration of aromatic C=C stretching), cm 1 (in plane bending for N H), 1380 cm 1 (O H in plane bending), cm 1 (C N aromatic amine), 944 cm 1 (O H out plane bending), C-Cl stretching at and cm -l, and 746 cm 1 (out plane bending for N H) 5,18,31. PEG 4000 based Aceclofenac solid dispersions In figure (5), The spectrum of PEG 4000 showed, important bands at 2890 cm -1 of C-H (aromatic ring)stretching, & cm -1 of C=C (aromatic ring) stretching,c-o (ether) stretching at 1125 cm - 1 and large band between 3483 cm -1 and 3119 cm -1.Addition of such polymers to pure AC resulted in no shift of any of these characteristic bands, indicating no chemical interaction between the drug and the polymers used 77,78. The peak of C=O (carbonyl) band at cm -l is disappeared in AC/PEG 4000 solid dispersions. The reason might be interaction of O-H of AC and oxygen atom in PEG The interaction is also possible between the acidic group of drug and carbonyl group of carrier in hydrogen bonding. The absorption bands which can be assigned to the free O-H and involved in intra-molecular hydrogen bonding of N-H at 2970 cm -1 is disappeared 5. However, although little shifts in the stretching vibration due to CH2 groups of PEG 4000 appeared at wave numbers 2890 cm -1 suggesting possible difference in the degree of interaction between AC and PEG Interestingly, C=O, N H, and O H bands in the spectra of ternary and quaternary SD incorporated with Na2CO3 disappeared, indicating an interaction between drug and ph modifier that enhanced drug dissolution rate 4. PVP K30 based Aceclofenac solid dispersions The spectrum of PVP showed, important bands at 2925 cm -1 (C-H stretch), 1655 cm -1 carbonyl group C=O and 1284 cm -1 (C N band for tertiary amines >N-group) as shown in figure (6). A very broad band was also visible at 3400 cm -1 which was attributed to the presence of water confirming the broad endotherm detected in the DSC experiments revealed the hygroscopic nature of PVP 79. FTIR results revealed that hydrogen bonding between AC and PVP supported the formation of AC/PVP solid dispersions. Each pyrrolidones moiety of PVP has two groups the carbonyl group and ternary amines that can potentially hydrogen bond with the amide (N-H) group or protonated pyridine N atom of AC 80.In spite of the broad peak at about cm -1 from PVP, the FTIR spectra of physical mixtures still showed small peaks of N- H or O-H stretching vibrations at the same position as that of AC. The spectra of physical mixtures were equivalent to the spectra obtained by the addition of polymers and the crystalline drug spectrum. This indicated that no interaction occurred with simple physical mixing of drug and hydrophilic polymers. Solid dispersions showed slightly different FTIR spectra in the fingerprint regions, the substantial differences were shown in the N-H or O-H stretching regions. This region was expanded to show differences between the spectra in figure (6). The largest spectral differences in this region were also reported for polymorphs of some compounds which reflected the different hydrogen bonding networks 81,82. However; broader and less intense peak of NH group of Aceclofenac (at cm -1 ) or an absence of ternary amide peak of PVP (at 1284 cm -1 ) may suggest intermolecular hydrogen bonding between AC and PVP in solid dispersion 9.The intense carbonyl band of PVP at 1655 cm -1 decreased and slightly shifted in AC/PVP dispersions. This was a clear indication of involvement of OH-groups of AC and carbonyl groups of PVP in the intermolecular hydrogen bonding, which might stabilize the amorphous structure of the AC/PVP dispersions 80. Conversely, frequently the carbonyl shift occurs to lower or higher wave numbers indicating specific drug PVP interactions have been also observed 80. The PVP based QSD and TSD with Na2CO3which showed to be X- ray amorphous gave no peak of this N-H stretching vibration. Comparing with AC and physical mixtures, the disappearance of these peaks was indicating the presence of intermolecular hydrogen bonds between AC and Na2CO3 4. The intermolecular hydrogen bond might be stronger than the others; therefore the N-H stretching might be weakened, resulting in a weak and broad peak that was completely covered by bond stretches from PVP. This FTIR pattern was previously observed for the N-H stretching of the amorphous Piroxicam-PVP solid dispersion 82,83. HPMC E5 based Aceclofenac solid dispersions HPMCspectrum showed; the peak at 3500 to 3400 cm -1 was due to OH vibrationalstretching.the symmetric stretching mode of methyland hydroxypropyl groups was found in the range 2900 cm -1 in which all the CH bonds extend and contract in phase as in figure (7). The peak at cm -1 was assigned tooh stretching vibration, i.e., O-Hand intramolecular hydrogen bonding. The band between 1650 and 1600 cm -1 indicated the presence of stretching vibration of C-Ofor six membered cyclic rings. Two bending vibrations might occur within a methyl group. The first of these, the symmetric bending vibration of methylinvolved the in-phase bending of the C-H bonds. The second, the asymmetric bending mode of methylwas due to outof-phase bending of the C-H bonds. While the asymmetric bending vibrations of the methoxy group normally appeared in the region cm -1, the symmetric vibrations were mostly displayed in the range cm The band between 1400 and 1350 cm -1 suggested C-O-Cof cyclic anhydrides. The peak at cm -1 was due toc-o-ccyclic epoxide. The band at cm -1 was for stretching vibration of ethereal C-O-C groups. The peak at cm-1 was due to pyranose. The rocking mode of CH2 was found in the range cm -1. The computed frequencies of HPMC are in a good agreement with experimental frequenciesfor both carbohydrate region as well as OH and CH region 85 The spectra of physical mixtures were showed no interaction occurred with simple physical mixing of drug and hydrophilic polymers.the spectra of HPMC based solid dispersion showed these distinct absorption bands of Aceclofenac and HPMC.The absence of any significant change in the IR spectral pattern in the formulations containing the drug and carriers indicated the absence of interaction between the drug and carriers employed for the solubility enhancement. On the other hand; the incorporation of Na2CO3to HPMC based TSD and QSD showed disappearance of the carboxylic acid O H peak indicated that it could be deprotonated by some ph modifier via a Bronsted acid base interaction 4,20. So; FTIR spectra showed a molecular interaction between AC and ph modifier, resulting in changes in drug crystallinity and dissolution. Inutec SP1 based Aceclofenac solid dispersions Inutec SP1 spectrum showed N H, O H, C=O, and C N bands at 3242, , 1755 and 1284cm -1 respectively as in figure (8).Similar to HPMC physical mixture and solid dispersion; Adding or incorporation Inutec SP1 did not affect the Aceclofenac bands. This indicated the absence of interaction between the drug and carrier. Also; the ph modifier had the same effect that observed with other polymers. This indicated molecular interaction that explains solubility and dissolution behavior. 566

14 Fig. 5: FTIR spectra of pure Aceclofenac, physical mixture (PM) with PEG 4000 andits solid dispersions Fig. 6: FTIR spectra of pure Aceclofenac, physical mixture (PM)with PVP K30and its solid dispersions 567

15 Fig. 7: FTIR spectra of pure ac, physical mixture (PM)with HPMC E5 and its solid dispersions Fig. 8: FTIR spectra of pure Aceclofenac, physical mixture (PM) with Inutec SP1 and its solid dispersions Scanning electron microscopy SEM photomicrographs are shown in figure(9) with Aceclofenac exhibited as crystalline particles while QCDs in a ratio (1:1:1:1) were amorphous particles. The pure Aceclofenac was characterized by crystals with bigger size and regular shape with an apparently smooth surface. Each QSD formulation showed one type of amorphous particles with a unique surface morphology unlike pure Aceclofenac. This suggested that the all components were homogeneously distributed in the formulations and a solid solution was formed which could be responsible for the increased dissolution rate of Aceclofenac. These results of were confirmed in DSC thermograms and XRD diffractograms. 568

16 Fig. 9: scanning electron microscope photomicrograph of Aceclofenac, PEG-QSD, PVP-QSD and HPMC-QSD formulations CONCLUSIONS In this study; two factors were used to optimizing Aceclofenac solid dispersion. These factors were controlling microenvironment ph of solid dispersion and preventing precipitation of AC. Polymers among all type of carriers used in this study showed the greatest effect on Aceclofenac solubility and dissolution. Preparations of solid dispersions were changed of drug crystallinity into an amorphous form by using different type of polymers. Na2CO3as ph modifier was controlling the microenvironment ph that enhanced solubility and initial drug dissolution. Inutec SP1 as a surfactant and precipitation inhibitor was achieved the goal of enhancing solubility and preventing precipitation of AC after initial enhancement of drug dissolution. The current QSD systems containing polymer, precipitation inhibitor and ph modifiercan enhance dissolution rates of ionizable and poorly water soluble drugs by the four major mechanisms: modulating microenvironment ph, changing drug crystallinity into an amorphous form via molecular interactions, increase wettability and prevent precipitation of drug that providing more favorable solid dispersion form for different type of tablets in a different ph. REFERENCES 1. Yu, L.X. et al. Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharmaceutical research 19, (2002). 2. Polli, J.E. et al. Summary workshop report: Biopharmaceutics classification system Implementation challenges and extension opportunities. Journal of pharmaceutical sciences 93, (2004). 3. Yu, L.X. Pharmaceutical quality by design: product and process development, understanding, and control. Pharmaceutical Research 25, (2008). 4. Tran, T.T.D., Tran, P.H.L. & Lee, B.J. Dissolution-modulating mechanism of alkalizers and polymers in a nanoemulsifying solid dispersion containing ionizable and poorly water-soluble drug. European Journal of Pharmaceutics and Biopharmaceutics 72, (2009). 5. Deshmukh, K.R. & Jain, S.K. Development of Aceclofenac Mouth Dissolving Tablets using Solid Dispersion Technique: In-vitro Evaluation. Indian Journal of Pharmaceutical Education and Research 46, (2012). 6. Aejaz A, Azmail K, Sanaullah S, Mohsin AA Formulation and invitro evauluation of aceclofenac solid dispersion incorporated gels. International Journal of Applied Pharmaceutics 2, 7 12 (2010). 7. Dahiya, S. Studies on formulation development of a poorly water-soluble drug through solid dispersion technique. Thai Journal of pharmaceutical Sciences 34, (2010). 8. Gupta, S. &Saini, L. Effect of lyophilization and polymer compositions on solubility of aceclofenac solid dispersions. Journal of Advanced Pharmacy Education & Research 2, (2011). 9. Rupal, J., Kaushal, J., Mallikarjuna, S.С. &Dipti, P. Preparation and Evaluation of Solid Dispersions of Aceclofenac. International Journal of Pharmaceutical Sciences and Drug Research 1, (2009). 10. Aleem, M., Dehghan, M. & Rajesh Babu, V. Solid Dispersion-An approach to enhance the dissolution rate of Aceclofenac by using 3 2 Factorial Design. International Journal of Pharmaceutical Sciences and Research 1, (2010). 569