INTRODUCTION:

In pharmaceutical research and development an increasing number of drug candidates are poorly water soluble. The solubility and dissolution may become rate limiting factors for effective bioavailability of such drugs upon oral administration¹. INDO, a non-steroidal anti-inflammatory drug used to reduce pain and swelling involved in osteoarthritis, rheumatoid arthritis, bursitis, tendinitis, gout, ankylosing spondylitis and headaches². It is described as BCS Class II drug³. Formulation development of poorly soluble drug is one of the major problems in pharmaceutical research. Water-insoluble drugs show low absorption and poor bioavailability thus there is a need of an improvement in solubility and/or dissolution rate in the development of Class II drug formulations⁴. INDO show low and erratic oral bioavailability due to poor dissolution of the drug in the fluids of the gastrointestinal tract (GIT).

Additionally, there may be increased incidences of irritating side effects on the GIT because of a prolonged contact time with the mucosa⁵. An enhancement of the dissolution rate of water-insoluble drug remains one of the most challenging tasks of drug development, because it can increase drug oral bioavailability. It is well established that the solubility and the bioavailability of a poor water soluble drugs can be improved by converting these drugs into an amorphous state⁶. Several methods such as freeze-drying⁷, spray-drying^{8, 9}, melting and quench-cooling¹⁰, melt extrusion and mechanical activation (milling)¹¹ have been reported to successfully prepare amorphous forms of drugs.

Formulation of SDs is another strategy used to increase the solubility and dissolution rate of drugs¹². The SD technique for water-insoluble drugs provides an efficient solution to improve the dissolution rate of a drug¹³. According to Chiou and Riegelman SD is dispersion of one or more active ingredients in an inert carrier or matrix, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Reported literatures indicate that polymeric carriers have been employed for enhancing the aqueous solubility of insoluble drugs¹. Drugs molecularly dispersed in polymeric carriers may achieve the highest levels of particle size reduction and surface area enhancement, which result in improved dissolution rates¹⁴. Polymers such as polyethylene glycol (PEG) and PVP have been extensively used as carriers for dispersions due to their low melting point and hydrophilic nature¹⁵. Methods used to produce SDs include melting method, solvent method and solvent wetting method. However, the melting method has limitations that incomplete miscibility between drug and carrier due to the high viscosity of a polymeric carrier in the molten state and thermally unstable drugs can be degraded due to the requirement of relatively high preparation temperatures¹⁶.

The first reported literature on application of solvent evaporation method was preparation of SDs of β-carotene with carrier PVP using chloroform¹⁷. Basically, solvent evaporation method involves two steps (i) preparation of a solution containing both matrix material or carrier and drug and (ii) the removal of the solvent resulting in the formation of the solid mass¹⁶. Nature of the solvent used and the rate and temperature of evaporation are critical factors that can affect the formed mass¹⁸. One of the unique features of this method is that thermal decomposition of the drugs can be prevented as low temperature is required for the removal of the organic solvents¹⁹. Till date solvent evaporation method has been reported for valdecoxib²⁰, carbamazepine²¹, fexofenadine hydrochloride²², and glibenclamide²³, etc. The literature reported reveals the successful application of this method for improvement in dissolution of poor water soluble drugs. Manimaran et al., in 2010, prepared the SD of glibenclamide by the solvent evaporation method using PVP, PEG and POLO as hydrophilic carrier. In this study, hydrophilic carriers enhanced the solubility of glibenclamide to a varying degree. All SDs increased dissolution rate compared to pure glibenclamide²⁴. Although use of SD has been reported frequently in the field of pharmaceuticals, only few SD systems are used commercially¹⁶.

INDO is rapidly absorbed after oral administration but since it has poor aqueous solubility its dissolution rate is very low⁵. In this research work, we used solvent evaporation method to prepare the SDs of INDO using different concentrations of PVP and POLO. Methanol was used because it is common solvent for INDO and carriers. The physicochemical properties of different systems were determined from SEM, DSC and XRPD studies. In addition, the effect of carrier concentration on dissolution properties of INDO in SDs was investigated.

MATERIALS AND METHOD:

INDO was a gift sample by Lupin Research Park, Pune. POLO and PVP were gift samples by Colorcon Asia Pvt. Ltd. Goa India. All other chemicals used were of analytical grade.

Preparation of PMs and SDs:

PMs of INDO with PVP or POLO at 1:2.5, 1:5, 1:7.5 and 1:10 weight ratio of INDO:carrier was prepared by blending with trituration for 10 min followed by sieving (500 μm). Compositions for SD were selected based on literature reviewed. SD of INDO at various weight ratios were prepared by solvent evaporation method. The amount of carrier was varied keeping amount of INDO constant. INDO was dissolved in sufficient quantity of methanol followed by addition of PVP or POLO to form homogenous mixture. These mixtures were evaporated at room temperature for 24h to obtain solid mixture and were pulverized. The pulverized powder was passed through 200-μm sieve. The samples were kept in desiccators until the next experiments.

Practical Yield and Drug Content:

Generally, percentage practical yield (%PY) is calculated to know about the efficiency of any method, thus it helps in selection of appropriate method of production. SDs was weighed to determine practical yield and %PY was calculated. SDs equivalent to 10mg of INDO were accurately weighed and dissolved in 10mL of methanol. The solution was filtered, diluted suitably and drug content was determined from absorbance at λ_max 318nm by spectrophotometric method.

Saturation Solubility:

An excess amount of the sample was placed in simulated gastric fluid (SGF) (0.1N HCl; pH 1.2) and simulated intestinal fluid (SIF) (phosphate buffer; pH 7.4). The samples were shaken for 48h at 37°C in a horizontal orbital shaker. The supernatant was filtered through a Millipore filter (pore size 0.45μm). Accurately measured 0.5mL of the filtrate was immediately diluted and assayed spectrophotometrically (Model V-7100 Jasco, Japan) at λ_max 318nm. All experiments were conducted in triplicate.

SEM Analysis:

The samples were coated with a thin gold layer by sputter coater unit (SPI, sputter, USA). SEM photographs were captured by a scanning electron microscope (Joel JSM 5400LV SEM, Japan) operated at an acceleration voltage of 15kV.

DSC Analysis :

The powdered samples (3-7mg) were hermetically sealed in aluminum pans and heated at a constant rate of 10°C/min, over a temperature range of 25°C to 200°C. Thermograms of the samples were obtained using DSC (DSC-60, Shimadzu, Japan). Thermal analysis data was recorded using a TA 50I PC system with Shimadzu software programs. Indium standard was used to calibrate the DSC temperature and enthalpy scale. Nitrogen was used for purging at a rate of 30mL/min.

XRPD Analysis :

XRPD studies have been widely used to understand crystallinity of solids. The samples were placed in the cavity of the metal sample holder of x-ray diffractometer and smoothened with a spatula. Samples were irradiated with monochromatised Cu Kα radiation (1.542Å) and analyzed between 5°2θ to 50°2θ employing a Philips FW 1700 X-ray diffractometer (Philips, Netherlands). The voltage and current used were 40kV and 30mA, respectively. The scanning rate was 0.04º2θs^-1.

In Vitro Dissolution Studies:

The USP dissolution test type II apparatus (Electrolab TDT-06N, India) was used. Amount of samples equivalent to 10mg of drug were dispersed into the dissolution vessel containing 900mL of SGF or SIF maintained at 37°C±0.5°C with a stirring speed of 50 rpm. Samples were withdrawn periodically, filtered and replaced with a fresh dissolution medium. After filtration through 0.45um microfilter, concentration of INDO was determined spectrophotometrically at λ_max 318nm. All experiments were carried out in triplicate.

RESULTS AND DISCUSSION:

Total eight formulations were prepared. Percent practical yield and drug content in SDs was in the range of 87.54% - 91.79% and 95.91% - 96.66%, respectively. Composition containing INDO: POLO at ratio 1:10 shown highest percentage yield and drug content.

Solubility Determination:

The aqueous solubility of a drug is a prime determinant of its dissolution rate and compounds with aqueous solubility less than 0.1 mg/ml often present dissolution limitation to absorption. INDO has pKa 4.5 and is practically insoluble in SGF (pH 1.2) and slightly soluble in SIF (pH 7.4). The solubility of INDO in phosphate buffer pH 7.4 was markedly increased in presence of PVP or POLO (Table 1). The solubility of INDO at 37°C±0.5ºC increased 5 folds and 6 folds in pH 1.2 and pH 7.4 when it was formulated as SD at 1:10 ratio in POLO, respectively. In case of SDs in PVP solubility in pH 1.2 and pH 7.4 solutions was increased by about 3-folds. In general, the increase in solubility of INDO was greater in SDs than in PMs.

Table 1: Solubility and thermal properties of pure INDO and INDO-carrier systems:

System	Ratio		INDO-POLO					INDO-PVP
		Solubility (mg/mL) in SGF (pH 1.2)	Solubility (mg/mL) in SIF (pH 7.4)	Temperatures (ºC)		Solubility (mg/mL) in SGF (pH 1.2)	Solubility (mg/mL) in SIF (pH 7.4)		Temperatures (ºC)
		Solubility (mg/mL) in SGF (pH 1.2)	Solubility (mg/mL) in SIF (pH 7.4)	Onset	Peak	Solubility (mg/mL) in SGF (pH 1.2)	Solubility (mg/mL) in SIF (pH 7.4)		Onset	Peak
INDO	1:0	0.127	0.312	150.65	162.33
POLO	0:1	--	--	43.51	54.30	--	--		--	--
PVP	0:1	--	--	--	--	--	--		141.35	150.17
PM	1:2.5	0.194	0.263	43.10	54.25	0.114	0.198		141.00	150.06
	1:5	0.215	0.271	43.16	54.11	0.185	0.241		141.27	150.08
	1:7.5	0.256	0.323	43.01	54.06	0.234	0.299		140.21	149.99
	1:10	0.284	0.355	42.78	53.65	0.260	0.324		140.36	149.67
SD	1:2.5	0.324	0.846	30.14	53.19	0.305	0.558		132.25	149.12
	1:5	0.451	0.963	37.00	51.40	0.352	0.662		134.11	147.01
	1:7.5	0.556	1.347	35.10	48.87	0.381	0.748		134.66	144.12
	1:10	0.660	1.791	38.65	48.50	0.410	0.930		134.15	143.66

Table 2: The percent drug dissolved and relative dissolution rates after 60 min of INDO, PMs and its SDs in POLO or PVP prepared by solvent evaporation method at different drug: carrier ratios:

Dissolution medium	Carrier	Ratio	PM		SD
Dissolution medium	Carrier	Ratio	% drug dissolved	Relative dissolution rate	% drug dissolved	Relative dissolution rate
SGF (pH 1.2)	INDO	1:0	6.6	1.0	6.6	1.0
	POLO	1:2.5	7.75	1.17	13.8	2.09
		1:5	8.81	1.33	17.7	2.68
		1:7.5	9.98	1.51	26.9	4.07
		1:10	13.83	2.09	28.2	4.27
	PVP	1:2.5	6.91	1.04	13.2	2.0
		1:5	7.63	1.15	16.9	2.56
		1:7.5	8.21	1.24	25.0	3.78
		1:10	10.1	1.53	26.4	4.0
SIF (pH 7.4)	INDO	1:0	40.2	1.0	58.5	1.0
	POLO	1:2.5	53.8	1.33	81.3	1.38
		1:5	64.25	1.59	90.3	1.54
		1:7.5	71.51	1.77	98.6	1.68
		1:10	84.77	2.10	99.8	1.7
	PVP	1:2.5	50.4	1.25	71.0	1.21
		1:5	60.13	1.49	86.0	1.47
		1:7.5	66.39	1.65	96.4	1.64
		1:10	75.2	1.87	99.5	1.69

The results of solubility study revealed that solubility increases with increase in concentration of carrier. Reasons for this might be improved wettability and porosity, decreased primary particle size and partial amorphization of drug in dispersed state compared to raw crystals of INDO²⁵. Enhanced solubility and dissolution rate of INDO in SD prepared using POLO could be attributed to the chemical structure of highly water soluble POLO. POLO has amphiphilic structure and ability to form monomolecular micelles by changing configuration in solution. At higher concentration, these monomolecular micelles associate to form aggregates of varying size, which has the ability to solubilize drug²⁶. Results indicated that POLO had solubilizing effect higher than PVP. This is attributed to the higher extent of disruption of crystallinity of INDO by POLO than by PVP²⁷.

In Vitro Dissolution Study:

Drug release studies were carried out in SGF (Fig. 1 and Fig. 3) and SIF (Fig. 2 and Fig. 4). The release of INDO in SIF was higher than that in SGF. The result was explained on the basis of the limited solubility of INDO in acidic medium. Blending of INDO with carriers in the form of PMs or SDs could enhance the release of INDO. The faster dissolution rate of PMs compared to pure drug was observed in case of both the carriers and could be attributed to the improvement of wettability of INDO particles due to the presence of highly hydrophilic molecular components. Dissolution rates for SDs were greater than those for PMs and INDO alone. The enhanced dissolution rates of INDO in SDs may be due to reduced particle size and specific form of drug in these SDs in addition to the increase in drug wettability and prevention of drug aggregation by these carriers. In the dispersed state INDO get entrapped into the hydrophilic coat of carriers and its crystallinity changes with change in its physicochemical properties²⁸. Both POLO and PVP changed crystalline drug to amorphous enhancing the dissolution rate. This observation is supported by the XRPD studies of the SDs. It is well known that amorphous drugs dissolve rapidly²⁹.

Figure 1. Dissolution profiles for INDO and INDO-POLO systems in SGF (pH 1.2)

Figure 2. Dissolution profiles for INDO and INDO-POLO systems in SIF (pH 7.4)

Figure 3. Dissolution profiles for INDO and INDO-PVP systems in SGF (pH 1.2)

The amount of INDO dissolved and relative dissolution rates after 60 min of INDO, PMs and its SDs in POLO or PVP prepared at different drug: carrier ratios are illustrated in Table 2. The highest amount of drug dissolved from PMs at pH 1.2 was 13.83% and the relative dissolution rates were in the range 1.04 – 2.09. In case of SDs of the carriers used the highest amount of drug dissolved was 28.2% with relative dissolution rates in the range of 2 – 4.27. On the other hand, at the pH 7.4 the highest amount of drug dissolved after time period was 84.77% and the relative dissolution rates were in the range 1.25 – 2.1 for PMs. In SDs of the carriers used the amount of drug dissolved was 99.87% and the relative dissolution rates were in the range of 1.21– 1.7. The percentage drug dissolved and relative dissolution rates at pH 1.2 and pH 7.4 were different according to the carriers used.

Figure 4. Dissolution profiles for INDO and INDO-PVP systems in SIF (pH 7.4)

Scanning Electron Microscopy:

SEM photographs of INDO, POLO, PVP and their corresponding PMs and SDs are shown in Fig. 5 and Fig. 6. The drug crystals seemed to be irregular and of different shape and size. Particle size of INDO crystals was much smaller than particles of POLO or PVP. The PM of the drug and carrier showed the presence of drug with partial loss of drug’s crystallinity. This loss may be attributed to development of physical interaction between drug and carrier during trituration. The carrier particles were easily differentiated from that of drug despite the reduction in size of particles of carriers during mixing and its presence in high amount (1:10 ratio). It was difficult to distinguish the INDO crystals in its SDs. INDO crystals appeared to be coated by the particles of the carriers. The SD looked like a porous matrix due to dispersion of the drug in the carrier solution.

Figure 5. SEM micrographs for different systems: INDO, POLO, PM and INDO: POLO SD (1:10)

Figure 6. SEM micrographs for different systems: INDO, PVP, PM and INDO: PVP SD (1:10).

Differential Scanning Calorimetry:

Thermograms of INDO, POLO and its PMs and SDs in POLO are shown in Fig. 7. The thermogram of pure INDO has shown a sharp endotherm at 162.33°C which represents its standard melting point. The endothermic peak at 54.3ºC is characteristic melting peak of POLO. In thermogram of PM (1:10), endothermic peak was observed at 53.65°C with the loss of its sharp appearance. The broadening and shifting of peak towards the left side shows the partial conversion into its amorphous form²⁹.

Figure 7. DSC thermograms: INDO, POLO, and their different systems

Figure 8. DSC thermograms: INDO, PVP, and their different systems

Endothermic melting peaks in the thermograms of PMs and SDs at low ratios were shifted to left side with broadening. At higher ratio, thermal profiles of both PM and SD exhibited an endothermic peak corresponding to the fusion of the carrier. The absence of melting peak corresponding to melting of drug was supported by XRPD studies. The results suggested that INDO dissolved completely into carrier. Thermograms of INDO, PVP and their PMs and SDs are shown in Fig. 8. The endotherm of PVP displayed broad peak appeared at 150.17°C corresponding to its melting point. The thermal behavior of PMs and SDs of the drug were different. In case of PM (1:10), the melting peak of INDO (melting point 158ºC) was weekend, broadened with splitting and appeared at 149.67°C while it became disappeared completely in case of SDs. The differences in the thermal behavior of INDO in the form of PMs and SDs suggested the amorphization of drug dependent of the ratio of the carrier used when prepared as SDs. The thermal analysis indicated decrease in crystallinity of INDO in presence of higher proportions of carriers. All PMs and SDs in POLO or PVP exhibited endothermic peaks due to the fusion of POLO and PVP. This revealed the existence of both carriers in the crystalline state that was consistent with the appearance of diffraction peaks in the corresponding XRPD pattern.

XRPD Analysis:

XRPD studies were carried out to study transformations in the state of drug in its PMs and SDs. XRPD patterns for different systems are shown in Fig. 9 and Fig. 10 for INDO-POLO and INDO-PVP systems, respectively. The diffraction spectrum of pure INDO showed that the drug is highly crystalline powder and possesses sharp peaks at 11.6°, 16.4°, 19.6°, 21.7°, 26.89° and 29.3°2θ. This corresponds to the γ-crystalline form polymorph of INDO. Characteristic peaks of POLO appeared at 13.68°, 19.24°, 23.32° and 27.37°2θ. PVP showed no prominent peaks. All the principles peaks from POLO were present in their PMs, but with lower intensities. In the case of the PMs, diffractograms were simply the sum of pure components and no interaction could be detected between them particularly at lower ratio (1:2.5). In case of PM of INDO-POLO system at 1:10 ratio, there was a decrease in the intensity of INDO but the major peaks remained at the same positions. The intensity of peaks reflected their mutual concentration. The decrease in the intensity of the diffractogram in case of the SD appeared at 1:2.5 ratio and the peaks of INDO disappeared completely at 1:10 ratio. It could be attributed to the coating of its crystal lattice, because upon evaporation of solvent residual carrier forms a coat around crystals. There was no peak shifting associated to the carriers in PMs indicating formation of an insertion-type solid where drug molecules found place inside the structure of the carrier without or with a limited deformation of the original crystal lattice. This is common in mixtures of polymeric carriers with small amounts of low molecular weight drugs.

Figure 9. XRPD diffractograms: INDO, POLO and their different systems

Figure 10. XRPD diffractograms: INDO, PVP and their different systems

In case of SDs the intensity of the peaks of INDO diminished with the increase in polymer ratio. On the other hand, INDO-PVP SD, the INDO peaks remained viewed in higher ratio of PMs (1:7.5 and 1:10). These observations revealed that the amount of PVP is not sufficient to dissolve the INDO completely. The amorphization of INDO was observed in the SD of INDO-POLO at 1:10 ratio, than its PM at same ratio. The results indicated that both carriers transformed crystallinity of INDO into amorphous INDO by different degrees. The reduced peak intensities in XRPD patterns clearly indicate that the INDO appears amorphous. No new peaks could be observed suggesting the absence of chemical interaction between the drug and the carriers.

CONCLUSION:

The study demonstrates that dispersions of INDO into water-soluble carriers changed the crystallinity of INDO relative to the type and the amount of the carrier. The formation of INDO-POLO SD destroyed almost completely the crystallinity of the drug and represents a suitable modification for improving its solubility. Decrease in agglomeration of particles, increase in wettability and decrease in crystallinity of the drug contributed to faster dissolution rate. Preliminary results from this work indicate that preparation of INDO SDs by solvent evaporation method using hydrophilic polymer carrier POLO could be a promising approach to improve solubility and dissolution rate of INDO. The higher ratio of POLO (1:10) tested in this study was sufficient for conversion of INDO to amorphous form.

ACKNOWLEDGEMENT:

The authors express their gratitude to Lupin Research Park, Pune for providing INDO as gift sample for this research work. Authors are very thankful to Dr. H. N. More the Principal Bharati Vidyapeeth College of Pharmacy Kolhapur, Maharashtra, for providing all facilities to carry out this work.

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Received on 22.07.2012 Accepted on 20.08.2012

Asian J. Pharm. Tech. 2(3): July-Sept. 2012; Page 116-122