INTRODUCTION:

There is an increasing percentage of drug molecules in pharma development pipelines which can be classified as Class II (compounds having good permeability but poor solubility) and Class IV compounds (compounds having poor permeability and poor solubility) under Biopharmaceutics Classification System (BCS) due to the advent of novel technologies such as high-throughput screening, fragment-based drug discovery, or computational modelling.

Although, these advanced molecules exhibit superior potencies and specificities towards their receptors compared to their predecessors, many also possess inherent challenges in terms of oral delivery due to their low solubility and poor permeability¹. In pharmaceutical formulations development, water insolubility has always been a key obstacle which affects formulation stability and drug bioavailability. Poor solubility and dissolution rate of drugs presents one of the most challenging traits in formulation development².

Though oral drug delivery presents several advantages in terms of better patient compliance and is most preferred route of administration, still it presents several check points and dissolution in gastric lumen is potential bottle neck to finally reach its site of action via systemic circulation. Therefore, there is great interest among formulation scientists to develop reliable, efficient, cost effective and scalable methods to increase the aqueous solubility of BCS class II drugs. Common formulation strategies to tackle such challenge include pH adjustment, self-emulsifying drug delivery systems, particle size reduction, supercritical fluid processing, inclusion complexes, cosolvency, micellar solubilization, hydrotrophy, solid dispersions, nanosuspensions, cocrystals, water soluble prodrug or, complexes, and nanocrystallization^3-6. The choice of a particular method depends mainly on the physicochemical characteristics of drugs, carrier properties and their expected use.

In order to overcome poor solubility and to improve bioavailability the use of amorphous and nanocrystalline systems is growing. The formulation development of poorly soluble drugs by solid dispersion technology utilizing different polymeric carrier has been widely researched over the past four decades for solubility and related bioavailability enhancement. Amorphous solid dispersions generally require less energy to dissolve the solute contributing for higher apparent solubilities and thus higher dissolution rates. Therefore, these forms usually have improved aqueous solubility^7-9. Targeting homogeneous dispersion of the drug in a polymer matrix, polymer plays key role in stabilizing amorphous form of the drug and achieving solubility benefit^7,11,12. Drug-polymer miscibility and the interaction between them is essential to ensure molecularly dispersed homogeneous system and it often allows maximum stabilization of amorphous drug, regardless of the stabilization mechanisms^13-14. However, these amorphous systems of the drugs often present challenges in terms of their tendency to recrystallize during storage¹⁰. A number of formulation strategies are reported which deliver drugs in solid form induce super saturation in the gastro intestinal lumen. Drugs should be administered as high energy or, rapidly dissolving system to generate thermodynamically unstable system. Different drug particle engineering techniques like milling, cogrinding, freezing, melting, solvent evaporation, crystal engineering etc aim at generating such high energy system. In solid dispersion, the drug is present in the carrier matrix either in molecularly distributed form, in the form of amorphous aggregates or, small crystalline or, partially crystalline form. The amorphous state is reported to have more solubility as compared to crystalline state^16-18.

On account of the excess thermodynamic activities, amorphous form of the drug have a tendency to recrystallize through equilibrium supercooled liquid state by enthalpy relaxation, when stored at temperature below the glass transition temperature. It has been suggested that the translational molecular motions below glass transition temperature, though relatively slow, have a significant effect on the stability of these amorphous solid dispersions. There has not been much marketed product based on solid dispersion technology due to these stability issues. Nonetheless, solid dispersion technique is known to be an effective approach to keep drugs stable in the solid state, thereby improving the dissolution rate and oral absorption by inhibiting reprecipitation and/or recrystallization in supersaturated system¹⁵. The stabilization of this supersaturated state by preventing reprecipitation of the drug appears to be the key to improve oral absorption.

Lapatinib (LAP) is a potent and selective inhibitor of the epidermal growth factor receptor and human epidermal growth factor receptor 2 and it is marketed in its ditosylate salt, in form of a film-coated tablet (Tyverb/Tykerb)¹⁹. It is currently used in combination therapy with capecitabine or, letrozole for the treatment of HER2-positive advanced or, metastatic breast cancer^20-21. It is categorized under BCS class-II drug and possess suboptimal pharmacokinetic properties. Its oral bioavailability has considerable interpatient variability and significantly affected by food intake²². It is also evident from many research works that both low-fat and high-fat diets before LAP administration increase its systematic exposure^22-23. Besides food intake, gastric pH also influences LAP bioavailability. Higher gastric pH reduces LAP absorption; therefore, concomitant use of proton-pump inhibitors can decrease its bioavailability²⁴. The recommended dose of LAP is 1,250–1,500mg once daily, which means taking 5-6 tablets at once, reducing patient adherence to therapy. Increasing the bioavailability of LAP could reduce the dose. Thus, a novel formulation with high solubility and bioavailability is currently an unmet medical need.

The present work is an attempt to prepare solid dispersions of lapatinib utilizing different techniques with an objective to improve its dissolution. Rapid onset of action is desirable to provide effective therapeutic outcome. Therefore, it is necessary to enhance the aqueous solubility and dissolution rate of LAP to obtain faster onset of action, minimize the variability in absorption and improve its overall oral bioavailability.

MATERIALS AND METHODS:

Materials:

Lapatinib (LAP) was received from Natco Pharma Limited, Hyderabad, India. LAP is practically water insoluble compound with a melting point around 136^◦C to 140^◦C. The polymers: poly(methacrylic acid, ethyl acrylate) marketed under the trade name Eudragit^® L 100 55 and poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) marketed under the trade name Eudragit^® EPO were purchased from Evonik Industries whereas, Povidone K30 was supplied by DKSH India Pvt. Ltd. Hypromellose Phthalate (HPMCP HP 55) and Hypromellose Acetate Succinate (HPMC AS MF) were supplied by Shin Etsu. All the excipients were used as received. All other ingredients used were of pharmaceutical grade and solvents used were of HPLC grade. Water used in this study was purified by a Milli-Q Synthesis A10 system (Millipore, Billerica, MA) unless otherwise mentioned.

Methods:

Solubility parameter calculation:

The solubility parameter calculation was carried out by in-silico molecular modelling approach based on molecular dynamics. It aims to estimate the solubility for binary combinations of LAP with commonly used polymers. Solubility parameters using Van Krevelen methods, of both drug as well as the polymers were calculated in order to determine the theoretical drug/polymer miscibility²⁵.

Preparation of solid dispersions of LAP:

The techniques used for the preparation of the solid dispersions are fusion technique, solvent controlled coprecipitation technique, nano-precipitation and spray drying technique. In all the techniques, solid dispersions of LAP were prepared using polymers with different ionic characteristics like Eudragit^® EPO (cationic), Eudragit^® L 100 55 (anionic), HPMCP HP 55 (anionic), HPMC AS (anionic), and Povidone K 30 (non-ionic) at three different ratios of 1:1, 1:2 and 1:3 to prepare the solid dispersions of weakly basic lapatinib.

Fusion technique:

LAP and the respective polymers were mixed thoroughly in a mortar and pestle and weighed into a stainless steel container and heated initially to 80°C on oil bath and stirred continuously using a stainless steel rod until the blend softens and melts. The final temperature was about 160°C. The soft and molten mass was subjected for sudden cooling over an ice bath and then allowed to cool to room temperature (25°C±3°C). The solidified dispersions were milled approximately after 1 hour using a mixer grinder (Maple). The prepared samples were stored at 25°C in a desiccator. The resulting dried solid dispersion samples were characterized and analysed²⁶.

Solvent controlled coprecipitation technique:

LAP and the polymer were dissolved in N, N- Dimethyl acetamide (DMA). The solution was introduced at ambient temperature into the respective antisolvent kept under stirring at 2500 to 3000 rpm under a laboratory stirrer by spraying through a spray nozzle 1mm in diameter with a spray rate of 12 gm per minute. The DMA-antisolvent phase ratio was maintained at 1:12 (w/w). The resulting precipitate was separated by filtration through two layer of nylon filter cloth (200 mesh followed by 400 mesh) under vacuum. The resulting precipitate was washed with 9.0 liters of the respective antisolvents. The wet precipitate mass was dried in tray dryer at 50^°C for 9 hours. The resulting dried solid dispersion samples were characterized and analysed. The antisolvents used were 0.01 N HCl for preparations containing Eudragit^®L 100 55, HPMCP HP 55 and HPMC AS MF, 0.067 M Phosphate Buffer, pH 6.8 for Eudragit^®EPO containing preparation and water for Povidone K 30 containing preparation²⁶.

Nanoprecipitation technique:

LAP was dissolved in ethanol (99%). The anionic polymers like Eudragit^®L 100 55, HPMCP HP 55 and HPMC AS MF were dissolved in 0.067 M Phosphate Buffer, pH 6.8, Eudragit^®EPO was dissolved in 0.1 N HCl and Povidone K 30 was dissolved in water. The drug solution was added to the respective polymer solution by spraying at a rate of 12 gm/min under stirring at 500 to 700 rpm. This resulted in a colloidal dispersion of LAP. The mean size and size distribution of dispersions was determined by photon correlation spectroscopy using Zetasizer ZS 90 (Malvern Instruments, Malvern, UK). Each sample was diluted to a suitable concentration with filtered Milli-Q water. Analysis was performed at 25^oC with an angle of detection of 90^o. The mean size was directly obtained from the instrument. The drug polymer complex in the colloidal dispersions were further precipitated by addition of the corresponding antisolvent. The antisolvent used was 0.01 N HCl for preparations containing Eudragit^®L 100 55, HPMCP HP 55 and HPMC AS MF, 0.067 M Phosphate Buffer, pH 6.8 for Eudragit^®EPO containing preparations and water with few crystals of sodium chloride (0.05% w/v) for Povidone K 30 containing preparations. The resultant wet mass was separated by centrifugation process (Kubota^®, 7780 Japan) at 7000 rpm for 7 min. The wet precipitate were further separated by filtration under vacuum through two layer of nylon filter cloth (200 mesh followed by 400 mesh). The wet precipitate was dried in tray dryer at 60^°C. The resulting dried solid dispersion samples were characterized and analysed²⁶.

Spray drying technique:

LAP and polymers were dissolved in the respective solvents to prepare clear solution. The respective polymers were dissolved as per their ratio (w/w) of drug to the polymers in either single or, binary solvent system depending upon the solubility of drug and polymers (total weight of the sprayed solution was 100 gm). Ethanol was taken as primary solvent for preparations made from drug and Eudragit L 100 55, Eudragit EPO, Povidone K 30 whereas, preparations with HPMCP HP 55 were prepared by using ethanol: acetone at a ratio 50:50 ratio (w/w) as the solvent system. Spray dried products were prepared using the spray dryer (Labultima, LU 222 Advanced). Nitrogen flow rate, sample concentration, and pump speed were each set. Other process parameters were fixed (inlet temperature: 70°C to 80°C; nozzle tip: 0.5 mm). All spray dried products were further dried under vacuum overnight, and their residual solvent.

Characterization of the solid dispersions:

The solid dispersions were evaluated for angle of repose, bulk and tap density. Carr’s Index values and Hausner’s ratio were calculated from bulk and tap density data. The moisture content of the solid dispersions was analyzed by Karl Fischer (K.F) titration method. The porosity (%) was determined by liquid displacement method.

LAP content in all the samples of solid dispersions was analyzed by UV spectrophotometry. Required quantity of solid dispersion was dispersed in 5 mL of acetonitrile. The suspension was sonicated in an ultrasonic bath for 20 minutes and then centrifuged for 15 minutes at 2500 rpm. The supernatant was filtered through Nylon 0.45µm filter (Millipore Millex-HN). The filtrate was suitably diluted and the absorbance was read at 359 nm. A standard graph was plotted by measuring the absorbance of different concentrations of LAP in acetonitrile (2-12 mcg/mL). The correlation coefficient (R²) of the regression line was 0.9996. The drug concentration in the test solution was obtained from regression equation.

X-ray Powder Diffractometry (XRPD):

XRPD was performed with an X-ray diffraction system (PANalytical, X’Pert PRO diffractometer) using the detector pixcel. The powders were exposed to Cu-K_αradiation source at 45kV and 40 mA. Diffractions patterns were obtained in 2θ at a range of 2-50^o using 0.02^oC step size and 10^°/min scan speed. The measurement was done with the application of X’Pert Highscore.

In-vitro dissolution studies of the solid dispersions:

The in-vitro drug dissolution study of the solid dispersions were performed using an 8 station USP 23 dissolution testing apparatus, Type II (Electrolab, India, model TDT-08L). Polysorbate 80, 2% w/v solution in 0.1N HCl and 0.067 M Phosphate Buffer, pH 6.8 (± 0.1) were used as dissolution media. Solid dispersions equivalent to 125 mg of LAP was dispersed in 450 mL of dissolution media. The temperature was maintained at 37°C ± 0.5°C and the dispersion was stirred at 55 RPM. At predetermined time intervals 5 mL of samples were withdrawn, filtered through Nylon 0.45µm filter (Millipore Millex-HN) and analysed spectrophotometrically at 382 nm for the samples in 0.1 N HCl and 359 nm for the samples in 0.067 M Phosphate Buffer, pH 6.8. At each time of withdrawal, 5 mL of fresh corresponding medium was replaced. The cumulative amount of drug release was calculated from the regression line obtained for standard samples in 0.1N HCl as well as 0.067 M Phosphate Buffer, pH 6.8 (± 0.1).

Statistical analysis:

Statistical analysis was carried out for the dissolution profile obtained for the solid dispersions using fit factors described by Moore and Falnner²⁷, adopted by the Food and Drug Administration guidance for dissolution testing. Briefly, fit factors are model independent methods that directly compare the difference between percent drug dissolved per unit time for a test and a reference product. The statistical analysis was carried out to evaluate the dissolution profile by the calculation of similarity and dissimilarity factor. The similarity factor (f₂) was defined by Food and Drug Administration (FDA) as the ‘logarithmic’ reciprocal square root transformation of one plus the mean squared difference in percent dissolved between the test and references release profiles. Dissimilarity or, difference factor (f₁) describes the relative error between two dissolution profiles. It approximates the percent error between the curves.

RESULTS AND DISCUSSION:

Results:

Solubility parameter calculation [Hansen solubility parameters (δ)]:

Compounds with similar values of δ are likely to be miscible. It was demonstrated that compounds with a Δδ < 7.0 (MPa)^1/2were likely to be miscible. When the Δδ > 10(MPa)^1/2, the compounds were likely to be immiscible. The small difference between the calculated solubility parameters of the polymers and LAP indicated that LAP is likely to be miscible with the anionic polymers (results not disclosed).

Solid dispersions of LAP by solvent controlled coprecipitation technique:

The solid dispersion samples were prepared with the binary composition of LAP to the polymers in a ratio 1:1, 1:2 and 1:3 by solvent controlled coprecipitation technique utilizing Eudragit® L 100 55, HPMCP HP 55, HPMC AS MF, Eudragit® EPO and Povidone K 30 as the carrier agents’. This technique yielded reasonably good dry powders. The recovery of powders from the process was more than 50%. Higher polymer concentration even resulted above 70% recovery. This lower yield for few samples is attributed to the lower batch size with some loss during process. The LAP content of the solid dispersions ranged from 98-100% of the anticipated amount and the moisture content lies below 2.30 (% w/w). The results revealed reasonable compressibility and flowability characteristics. The results are recorded in table 1.

Solid dispersions of LAP by fusion technique:

The solid dispersion samples were prepared with the binary composition of LAP to the polymers in a ratio 1:1, 1:2 and 1:3 by fusion technique utilizing Eudragit^® L 100 55, HPMCP HP 55, HPMC AS MF, Eudragit^® EPO and Povidone K 30 as the carrier agents. This technique also yielded reasonably good dry powders. The recovery of powders from the process was more than 75%. The LAP content of the solid dispersions ranged from 97-100% of the anticipated amount and the moisture content for the solid dispersions lies below 3.0 (% w/w). The moisture content of LAP was observed to be 0.18%. The results revealed reasonable compressibility and flowability characteristics. The results are recorded in table 1.

Table 1. Physico-chemical characterization and micromeritics properties of solid dispersions of lapatinib.

S. No.		Technology		Polymer	Ratio		Sample Code	Yield (%)		MC (%)	Assay (%)	Compressibility property										% P	AR (°)
												BD (g/mL)				TD (g/mL)		CI (%)		HR
1		NA		NA	NA		LAP	NA		0.18	99.50	0.213				0.262		18.702		1.230		34.531	40.000
2		Solvent controlled coprecipitation		Eudragit L 100 55	R 1:1		LCPL1	62.00		1.58	98.94	0.238				0.313		23.810		1.313		69.959	30.000
3					R 1:2		LCPL2	67.50		1.75	99.04	0.238				0.294		19.048		1.235		71.935	32.000
4					R 1:3		LCPL3	86.50		2.11	99.14	0.227				0.304		25.239		1.338		74.285	32.000
5				Eudragit EPO	R 1:1		LCPE1	63.75		1.45	98.46	0.238				0.313		23.810		1.313		70.962	33.000
6					R 1:2		LCPE2	64.17		1.51	98.56	0.238				0.294		19.048		1.235		72.504	33.000
7					R 1:3		LCPE3	91.88		2.14	99.42	0.238				0.294		19.048		1.235		73.542	34.000
8				PVPK30	R 1:1		LCPP1	53.50		1.83	100.29	0.227				0.313		27.273		1.375		71.274	30.000
9					R 1:2		LCPP2	55.83		1.78	99.71	0.227				0.313		27.273		1.375		71.801	30.000
10					R 1:3		LCPP3	71.75		2.15	99.52	0.238				0.313		23.810		1.313		73.638	30.000
11				HPMCP HP 55	R 1:1		LCPHP1	61.25		1.55	99.90	0.238				0.313		23.810		1.313		72.518	30.000
12					R 1:2		LCPHP2	75.33		1.62	99.81	0.250				0.313		20.000		1.250		70.080	32.000
13					R 1:3		LCPHP3	85.88		2.17	98.94	0.238				0.313		23.810		1.313		72.532	32.000
14				HPMC AS	R 1:1		LCPAS1	66.50		1.72	99.04	0.238				0.313		23.810		1.313		73.576	32.000
15					R 1:2		LCPAS2	77.17		1.77	99.52	0.238				0.313		23.810		1.313		72.532	32.000
16					R 1:3		LCPAS3	90.50		2.28	98.08	0.238				0.313		23.810		1.313		70.977	33.000
17		Fusion		Eudragit L 100 55	R 1:1		LHML1	76.00		2.28	98.94	0.357				0.455		21.429		1.273		59.453	25.000
18					R 1:2		LHML2	88.28		2.31	99.14	0.417				0.500		16.667		1.200		55.159	25.000
19					R 1:3		LHML3	86.83		2.21	100.00	0.417				0.500		16.667		1.200		53.664	24.000
20				Eudragit EPO	R 1:1		LHME1	79.58		2.22	99.33	0.333				0.417		20.000		1.250		64.214	25.000
21					R 1:2		LHME2	93.56		2.36	99.52	0.356				0.417		14.560		1.170		63.413	25.000
22					R 1:3		LHME3	86.83		2.47	100.10	0.385				0.500		23.077		1.300		59.754	25.000
23				PVPK30	R 1:1		LHMP1	74.83		2.78	100.00	0.357				0.417		14.286		1.167		60.263	26.000
24					R 1:2		LHMP2	90.11		2.98	99.33	0.367				0.455		19.260		1.239		60.003	25.000
25					R 1:3		LHMP3	92.17		2.74	98.85	0.417				0.500		16.667		1.200		52.761	27.000
26				HPMCP HP 55	R 1:1		LHMHP1	78.50		2.25	99.81	0.357				0.417		14.286		1.167		60.263	26.000
27					R 1:2		LHMHP2	79.89		2.46	98.56	0.377				0.455		17.060		1.206		57.215	28.000
28					R 1:3		LHMHP3	89.75		2.32	100.10	0.417				0.500		16.667		1.200		53.640	25.000
29				HPMC AS	R 1:1		LHMAS1	82.25		2.21	98.75	0.333				0.417		20.000		1.250		62.931	25.000
30					R 1:2		LHMAS2	90.22		2.32	98.85	0.385				0.455		15.385		1.182		56.395	25.000
31					R 1:3		LHMAS3	89.25		2.47	97.02	0.385				0.455		15.385		1.182		58.062	25.000
	32		Nano precipitation	Eudragit L 100 55	R 1:1		LNPL1	43.75		2.47	99.90	0.250				0.313		20.000		1.250	68.437		32.000
	33				R 1:2		LNPL2	61.50		2.88	100.19	0.278				0.313		11.111		1.125	67.258		32.000
	34				R 1:3		LNPL3	78.13		2.67	99.62	0.278				0.314		11.667		1.132	66.106		32.000
	35			Eudragit EPO	R 1:1		LNPE1	53.50		2.84	100.10	0.238				0.299		20.476		1.257	70.962		33.000
	36				R 1:2		LNPE2	63.00		2.91	99.52	0.270				0.303		10.811		1.121	68.200		32.000
	37				R 1:3		LNPE3	65.13		2.84	100.10	0.272				0.307		11.413		1.129	67.445		31.000
	38			PVPK30	R 1:1		LNPP1	58.00		2.64	100.00	0.250				0.313		20.000		1.250	68.402		32.000
	39				R 1:2		LNPP2	52.83		2.81	99.33	0.278				0.313		11.111		1.125	65.524		33.000
	40				R 1:3		LNPP3	62.38		2.84	98.56	0.278				0.317		12.500		1.143	66.106		32.000
	41			HPMCP HP 55	R 1:1		LNPHP1	65.50		2.47	97.60	0.267				0.316		15.508		1.184	66.798		31.000
	42				R 1:2		LNPHP2	52.83		2.64	98.85	0.275				0.329		16.484		1.197	65.294		32.000
	43				R 1:3		LNPHP3	70.75		2.54	100.00	0.275				0.329		16.484		1.197	66.478		31.000
	44			HPMC AS	R 1:1		LNPAS1	53.75		2.65	97.21	0.238				0.299		20.476		1.257	71.462		32.000
	45				R 1:2		LNPAS2	63.00		2.78	97.60	0.270				0.303		10.811		1.121	67.022		31.000
	S. No.		Technology	Polymer	Ratio	Sample Code		Yield (%)	MC (%)		Assay (%)			Compressibility property							% P		AR (°)
														BD (g/mL)	TD (g/mL)		CI (%)		HR
	46				R 1:3		LNPAS3	71.88	2.79		97.21		0.272		0.307		11.413		1.129		65.671		32.000
	47		Spray drying	Eudragit L 100 55	R 1:1		LSDL1	62.50	1.91		94.62		0.161		0.238		32.258		1.476		79.637		40.000
	48				R 1:2		LSDL2	70.00	2.11		97.69		0.167		0.227		26.667		1.364		80.355		42.000
	49				R 1:3		LSDL3	87.50	2.15		97.12		0.167		0.238		30.000		1.429		79.663		41.000
	50			Eudragit EPO	R 1:1		LSDE1	60.00	1.92		96.83		0.143		0.227		37.143		1.591		82.577		45.000
	51				R 1:2		LSDE2	68.33	2.21		96.54		0.152		0.227		33.333		1.500		82.172		46.000
	52				R 1:3		LSDE3	88.75	2.20		96.25		0.161		0.217		25.806		1.348		80.677		45.000
	53			PVPK30	R 1:1		LSDP1	55.00	1.95		98.27		0.152		0.208		27.273		1.375		80.850		45.000
	54				R 1:2		LSDP2	71.67	1.98		99.33		0.156		0.208		25.000		1.333		80.607		45.000
	55				R 1:3		LSDP3	90.00	2.11		98.17		0.156		0.208		25.000		1.333		80.934		45.000
	56			HPMCP HP 55	R 1:1		LSDHP1	62.50	1.91		96.54		0.143		0.192		25.714		1.346		82.261		45.000
	57				R 1:2		LSDHP2	75.00	2.24		96.64		0.143		0.227		37.143		1.591		81.953		45.000
	58				R 1:3		LSDHP3	88.75	2.24		99.52		0.152		0.217		30.303		1.435		81.512		45.000
	59			HPMC AS	R 1:1		LSDAS1	70.00	1.96		96.73		0.152		0.208		27.273		1.375		81.839		45.000
	60				R 1:2		LSDAS2	73.33	2.10		97.02		0.156		0.217		28.125		1.391		80.934		45.000
	61				R 1:3		LSDAS3	92.50	2.14		96.64		0.156		0.217		28.125		1.391		80.261		45.000

NA: Not applicable; MC: Moisture content, BD: Bulk density; TD: Tapped density, CI: Carr’s compressibility index, HR: Hausner’s ratio, AR: Angle of repose, P: Porosity

Solid dispersions of LAP by nanoprecipitation technique:

The solid dispersion samples were prepared with the binary composition of LAP to the polymers in a ratio 1:1, 1:2 and 1:3 by nanoprecipitation technique utilizing the same polymers as by the above technique. This technique yielded reasonably good dry powders. The recovery of powders from the process was in between 40% to around 78%. This lower yield for few samples is attributed to the lower batch size with some loss during process. The LAP content of the solid dispersions ranged from 97-100% of the anticipated amount and the moisture content for LAP and the solid dispersions was below 3.0 (% w/w). The results revealed reasonable compressibility and flowability characteristics. The results are recorded in table 1.

Solid dispersions of LAP by spray drying technique:

The solid dispersion samples were prepared with the binary composition of LAP to the polymers in a ratio 1:1, 1:2 and 1:3 by spray drying technique utilizing the same polymers as by the above technique. This technique yielded reasonably good dry powders. The recovery of powders from the process was in between 55% to around 92%. This lower yield for few samples is attributed to the lower batch size with some loss during process. The LAP content of the solid dispersions ranged from 94-100% of the anticipated amount and the moisture content for LAP and the solid dispersions was below 2.5 (% w/w). The results revealed reasonable compressibility and flowability characteristics. The results are recorded in table 1.

Characterization of solid dispersions:

The details of flow and compression characteristics of LAP and different solid dispersions samples are recorded in table 1. The solid dispersions showed comparable micromeritic, flow and compressible properties. The angle of repose for the drug powder LAP is obtained as 40°. For solid dispersions it ranged from 24° to 46°. The solid dispersions corresponding to fusion technique showed better compressibility indices than that of LAP which may be due to the hybrid denser particles of drug inside the polymer matrix. However, the samples corresponding to spray drying, possess poor flow property than that of other samples. This flow rate can be improved by using additional carrier in the spray drying procedure in addition to the polymer. The particles of the solid dispersions prepared by all the above mentioned techniques have reasonable porous nature; around 80% porosity was obtained for solid dispersions prepared by spray drying technique.

The presence of moisture is a crucial characteristic for the solid dispersions as they could induce instability. The solid dispersions possess moisture content less than 3.0% which shows that the solid dispersions may not suffer moisture driven stability issues.

The size of the dispersions corresponding to the solid dispersions by nanoprecipitation technique are observed and recorded in table 2 and the average size ranged from 100 nm to 720 nm. However, the polydispersibility index was high. The increase in polymer concentration led to higher particle size in the preparations corresponding to all the three polymers.

Table 2. Characteristics of different preparations of from lapatinib in Milli Q water in nanoprecipitation technique.

S. No.	Polymers	Ratio	Sample Code	Average size (nm)	Polydispersity index (PDI)
1	Eudragit L 100 55	R 1:1	LNPL1	101.2	0.529
		R 1:2	LNPL2	708.3	0.482
		R 1:3	LNPL3	718.4	0.552
2	Eudragit EPO	R 1:1	LNPE1	192.2	0.581
		R 1:2	LNPE2	241.5	0.311
		R 1:3	LNPE3	259.6	0.533
3	PVP K 30	R 1:1	LNPP1	146.4	0.299
		R 1:2	LNPP2	479.2	0.384
		R 1:3	LNPP3	495.6	0.53
4	HPMCP HP 55	R 1:1	LNPHP1	153.6	0.186
		R 1:2	LNPHP2	491.2	0.193
		R 1:3	LNPHP3	551.9	0.278
5	HPMC AS MF	R 1:1	LNPAS1	141.3	0.524
		R 1:2	LNPAS2	469.2	0.794
		R 1:3	LNPAS3	553.2	0.186

X-ray Powder Diffractometry (XRPD)

The extent of crystallinity affects dissolution of drugs. Generally, amorphous or, metastable form will dissolve faster because of its higher internal energy and greater molecular motion compared to crystalline materials. Crystallinity was determined by comparing some representative peak heights in diffraction patterns of the solid dispersions with those of pure drug. The XRPD pattern of LAP, placebo and the solid dispersions by different techniques is presented in Figure 1. The presence of numerous distinct peaks in the diffractrogram of LAP reveal the crystalline nature of LAP with characteristic diffraction peaks appearing at 18.75, 14.71 and 23.04.

(A)

(B)

(C)

(D)

Figure 1. X-ray powder diffraction pattern summarizing the comparative diffractogram of LAP, placebo and different solid dispersions prepared by (A) solvent controlled coprecipitation technique, (B) nanoprecipitation technique (C) fusion technique (D) spray drying technique.

The solid dispersions prepared by solvent controlled coprecipitation technique suggest that the sample containing lower concentration of all the five polymers; HPMC AS MF, HPMCP HP 55, Eudragit EPO, Eudragit L 100 55 and Povidone K 30 have shown the characteristic peaks of LAP in the diffractograms although the intensity is very low indicating partial crystalline nature. However, the higher concentration of the polymers resulted in the diminishing of the peaks for LCPAS3, LCPHP3 and LCPL3 (anionic polymers containing preparation) alluding about the amorphous nature of the samples. However the preparations with higher concentration of Eudragit^®EPO and Povidone K 30 have shown the characteristic diffraction peaks of LAP. On the other hand, amorphous nature was revealed for all the samples in fusion technique irrespective of the nature of the polymers. This may be due to the breaking of crystal lattice enrgy with the application of heat. The samples prepared with nanoprecipitation technique has shown different crystallinity behaviour. The samples corresponding to LNPE1, LNPE3 and LNPP1 have shown characteristic diffraction peaks of LAP due to their inadequate interaction with the polymers. However, lower ratio with anionic polymers also have shown amorphous nature. The samples prepared by spray drying technique have similar trend as that by nanoprecipitation technique and the lower ratio of anionic polymers have shown amorphous form of LAP; however higher ratio of Eudragit EPO and Povidone K 30 could not prevent crystallization.

In-vitro dissolution studies of the solid dispersions:

The powder dissolution data reported in Figure 2 and 3 shows that the dissolution profile of LAP as such was the lowest of all, with no more less than 5% dissolved within 2 hours in both the media. The presence of polysorbate 80 in the dissolution media also could not improve the dissolution of LAP. In comparison to this, the release of LAP was improved from different solid dispersions in both the dissolution media.

Solid dispersions prepared with anionic polymers viz. Eudragit^® L 100 55, HPMCP HP 55, HPMC AS MF have shown higher dissolution irrespective of the technique used. It reached near complete dissolution within 2 hours for the solid dispersions prepared with these anionic polymers. However, solid dispersions with HPMCP HP 55 were having slight edge over the other polymers. The dissolution appears to be higher and faster at higher polymer concentration. For dispersions prepared with Eudragit^®EPO and Povidone K 30 the extent of dissolution was much lower in all the four techniques.

The solid dispersions prepared with cationic polymer Eudragit^®EPO have shown a maximum dissolution of only 10% in pH 6.8 phosphate buffer and 12% in 0.1 N HCl. In the acidic medium 0.1 N HCl containing polysorbate 80, LAP as such showed similar extent of low dissolution. In this medium, preparations made with Eudragit^®EPO by fusion and spray drying techniques showed maximum dissolution of about 12% in 120 minutes. But the preparations prepared with the other two techniques, show significant drop up to 120 min indicating reprecipitation of the drug. The lower rate of dissolution with preparations corresponding to Eudragit^®EPO is expected at pH 6.8 since the polymer dissolves in acidic media. Thus, it should resist the drug release at pH 6.8. However, these preparations also show less dissolution in 0.1N HCl. The solid dispersions prepared with non-ionic polymer, Povidone K 30 have better release than that of the preparations with Eudragit^®EPO in both the media. The preparations with Povidone K 30 by solvent controlled coprecipitation resulted approximately 40% dissolution in about 45 minutes in 0.1 N HCl and about 58% release in about 90 minutes from the preparations by fusion technique in 0.067 M Phosphate Buffer, pH 6.8. In 0.1N HCl, solid dispersions with Povidone K 30 have shown the highest dissolution value of 41% with solvent controlled coprecipitation technique and around 12% with the other three techniques. In pH 6.8 phosphate buffer, better release was observed although reprecipitation of the drug was evident in the samples prepared with all the four techniques. Further, with both the above polymers, the dissolution dropped significantly after reaching a peak indicating drug precipitation. On the contrary, preparations made with anionic polymers did not show such drop.

For preparation made with anionic polymers, the extent of dissolution was found to be the highest in the dispersions made with all the four techniques. In 0.1 N HCl, preparations at a higher drug: polymer ratio resulted complete dissolution in 60 minutes for LHMHP3, LHMAS3; 90 minutes for LCPL3, LCPAS3, LHML3, LSDHP3 and 120 minutes for LCPHP3. However, in 0.067 M Phosphate Buffer, pH 6.8 preparations at a higher drug: polymer ratio resulted complete dissolution in 90 minutes for LCPL3, LCPAS3, LHML3, LSDHP3 and 60 minutes for LHMHP3, LHMAS3. The other preparations with the anionic polymers have also shown reasonable improvement in the release and identified without any sign of reprecipitation. The samples prepared with anionic polymers by nanoprecipitation technology have shown incomplete release however, the sign of reprecipitation was not observed. The drug polymer ratio had a significant influence on dissolution.

DISCUSSION:

The dissolution rate of the solid dispersions of LAP with different anionic polymers (especially HPMCP HP 55) is higher than that of pure LAP and the solid dispersions prepared with other two polymers (Eudragit EPO and Povidone K 30). The possible elucidations of the increased dissolution of solid dispersions over LAP have already been proposed by Craig and Ford, as reduction of drug crystallite size, a solubilization effect of the carrier, absence of aggregation of drug crystallites, improved wettability and dispersibility of the drug, dissolution of the drug in the carrier, conversion of the drug to the amorphous state and finally the combination of the above mentioned mechanisms^28-29. The dissolution mechanism of solid dispersion might be predominantly diffusion-controlled and presumably the high viscosity of this carrier in stagnate layer is the main factor to control the dissolution rate. In addition to the above mentioned mechanisms, the interaction of LAP with the anionic polymers also accounts for the higher dissolution rate. The dissolution profiles of solid dispersions with the anionic polymers showed an increase in the dissolution rate of LAP with respect to the drug by itself which could be due to the acidic nature of the polymer. The assumed hydrogen bonding between the –COOH group of the polymers with –NH group of LAP in the solid dispersions may be playing a vital role in the higher drug release. The predicted hydrogen-bond acceptors in LAP is interacting with the anionic polymers alluding about the effectiveness of the polymers inhibiting nucleation and recrystallization in a concentration dependent manner. It is also clear that increasing the weight fraction of LAP in the solid dispersions did not affect noticeably the dissolution rate of the solid dispersions. The supersaturation of lapatinib was effectively prolonged in the presence of different anionic polymers.

Generally, solid dispersions intent at resulting high and possibly supersaturated intraluminal concentrations of the drugs by increasing their apparent solubility and dissolution rate. In the dissolution media, LAP molecules are released by the dissolution of the carrier matrix or, codissolution of both LAP and the carrier matrix under the influence of polysorbate 80. This release can be explained by higher apparent solubility, polymer induced increased wettability and increased surface area for dissolution. Likewise, the performance of different solid dispersions is determined by the dissolution after oral administration. The fundamental aspect lying behind almost all solubilization technologies is the so called “spring-and-parachute” concept^30-35.

In-silico molecular modelling approach based on molecular dynamics can be used as a powerful tool to determine the drug-polymer interactions through both visualization and estimation of the strength of the interactions. It is evident from the in-silico studies that the anionic polymers interacts with LAP. The interaction is due to the hydrogen bond formation and/or hydrophobic interactions. The predicted solubility parameter, [δ (MPa)^1/2] was found to be less than 7 for LAP with anionic polymers with HPMCP HP 55 the lowest value of 0.793 (MPa)^1/2 was observed. This interaction has been well depicted by the solubility parameter showing that Δδ< 7.0 (MPa)^1/2 implying of better miscibility of the drug in the polymer. However, it should also be noted that the solubility of the drug in the polymer is not enough to prevent the recrystallization and improvement in the drug release. The hydrogen-bond acceptors in LAP may be interacting –COOH group of the anionic polymers and this determine the effectiveness of the polymers in inhibiting nucleation and recrystallization in a concentration dependent manner^36-38. Additionally, it is also expected that LAP will show better interaction with the anionic polymers due to the weakly basic nature of LAP. The different anionic polymers enhance release of weakly basic LAP in the dissolution media by lowering microenvironmental pH and thus maintaining higher local solubility of the drug.

The dissolution of LAP from the solid dispersions in both the media was variable and found to be dependent on its weakly basic nature and interactions with the polymers rather than merely amorphous transformation. For instance, the dissolution rate and the supersaturation levels of LAP were significantly improved using anionic polymers in spite of crystallinity detection by PXRD study. No dissolution improvement could be achieved using cationic and non-ionic polymers. The improvement of dissolution with anionic polymer could be attributed to stronger counter ionic interactions between LAP and different anionic polymers which could have occurred during the preparation of the solid dispersions. Further, the dissolution rates and the supersaturation levels of these solid dispersions were significantly higher than LAP.

It means that the drug should first dissolve along with the soluble polymer matrix to create a supersaturated solution (“the spring”) after which supersaturation is maintained long enough for drug absorption (“the parachute”) to take place. When solid dispersions are exposed to the aqueous environment of the gastrointestinal tract, supersaturated drug solution is being generated. Drugs in this state have a tendency to precipitate rapidly before being absorbed resulting in reduced bioavailability. The act of prevention of the reprecipitation and prolonging of supersaturation of the drug in the dissolution media can be judiciously arrested by utilizing different polymers like polymers like hydroxypropyl methylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) and vinyl polymers such as poly (vinylpyrrolidone) (PVP) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) which are employed not only as carriers for solid dispersions but are also meant for inhibiting drug precipitation. The different nature of the polymers utilized in this study like Eudragit^® EPO (cationic), Eudragit^® L 100 55 (anionic), HPMCP HP 55 (anionic), HPMC AS (anionic) and Povidone K 30 (non-ionic) are also reported to be potential crystallization inhibitors. However, the weakly basic nature of LAP resulted in effective interaction and thus the supersaturated drug concentration in the dissolution medium was maintained. Thus, the dissolution of LAP from the solid dispersions with anionic polymers is faster and complete and the supersaturated solution around the solid dispersions determines the concentration of the free drug. The water continuously penetrates into LAP solid dispersion particles due to the porous nature and finally resulting in the phase separation. However, the anionic polymers inhibited further growth in the crystallization and the supersaturation state is maintained for some time. It may be also understood that there may be interaction of LAP with the polymer or, changing the properties of the medium or both^31,
32or, suppressing the nucleation process³³ or, adsorbing on the surface of crystals to block the access of solute molecules (“the poisoning effect”) thus preventing or retarding crystal growth^{34, 35}.

The process of delaying of nucleation and inhibition of recrystallization may not be only due to the increase in the nucleation activation energy but also reduce crystal growth^39-41. Many researchers have discussed different characteristic features of drug and polymer in the hydrogen bonding interaction. The lipophilicity of the polymers, rigidity of the polymers, adsorption onto the crystal surface resulting in steric hindrance and few other factors have been discussed^42-49. The interaction via hydrogen bonding between the carboxyl group of the anionic polymer and -NH group of LAP was the basis for the interaction strength. In general, drug release from the solid dispersions occur in different possible ways like a) dissolution of drug and polymer in the solid dispersion in a rapid manner then subsequently undergo absorption and precipitation in the presence of polymer and endogenous compounds such as bile acids, phospholipids and mucin as described for low drug loaded solid dispersions and b) it is also explained that during this dissolution process, various structures may form including free drug (the major species, if not the only species, being absorbed, so its concentration is what matters for absorption), drugs in bile salt/phospholipid micelles, amorphous drug nanoprecipitates with polymers, and possibly drug nanocrystals stabilized with polymers, all of which are in dynamic exchange with each other⁵⁰. Overall, LAP dissolution characteristic is a resultant product of the above mentioned factors greatly influenced by miscibility and interaction with the corresponding polymers, dispersibility in the matrix and its particle size. Therefore, drug loading, matrix composition and preparation technique will dictate the initial degree of supersaturation. The degree of supersaturation depend upon the presence of codissolving matrix which act as precipitation inhibitor. Dissolution of anionic polymer in the media releases supersaturated concentration which is maintained for 2 hours.

We have attempted to achieve pH-independent release of LAP from polymeric matrices by incorporation of polymers of different ionic characteristics to compare the release behaviour. The solid dispersions prepared with anionic polymers are presumed to lower the release in the acidic environment by forming an insoluble mass which may act as barrier to drug diffusion and enhance release in a high pH environment. However, we observed that in spite of having low permeability of Eudragit^® L 100 55, HPMCP HP 55 and HPMC AS MF to 0.1N HCl significant improved release behaviour was observed for the solid dispersions with these polymers than the solid dispersions prepared from other polymers. LAP molecules could have been solubilized due to the acidity of the polymers and got released completely. Further, porosity of solid dispersion and presence of polysorbate 80 could have aided the drug release under different conditions. In the case of nanoprecipitation technique and few other samples, the drug is in crystalline form but the release is high. It is known that nano size of the particles affects the solubility and the dissolution. Thus, this form also appear to aid in creation of supersaturated state that is subsequently stabilized by the polymer.

We have attempted four novel techniques like solvent controlled coprecipitation, fusion, spray drying and nanoprecipitation for preparing the solid dispersions of LAP. In spite of having differences in the preparation procedure and other physico chemical properties, it was observed that judicious choice of polymer and technique are prerequisite of preparing solid dispersion formulation development of any drug. Drug-polymer interaction through hydrogen bonding or, any other electrostatic interaction play a get role in achieving drug-polymer miscibility and maintenance of super saturation in the gastric milieu for a period.

It is also evident that the presence of crystalline peaks in the diffractograms of different solid dispersions is not affecting the dissolution. The solid dispersions prepared with different concentrations of anionic polymers irrespective of the ratio have shown better release profile than the solid dispersions prepared from Eudragit^®EPO and Povidone K 30.

Porosity provides pathways for the penetration of fluid into the powder through capillary action and resulted in rupture of inter-particulate bonds causing the powder to break and change in the morphological form contributed to the dissolution velocity enhancement. The solid dispersions prepared from the solvent controlled coprecipitation, spray drying and nanoprecipitation techniques have shown higher porosity of 60 to 80%. However, the solid dispersions obtained from fusion technique exhibited lower porosity of 50 to 63% which is however higher than LAP itself (34.5%) and is attributed to the molten stringent polymer layer on the particles.

The release behaviour indicate solubilisation which is related to the ionic nature of the polymer. The polymer-specific properties of Eudragit^®L 100 55, HPMCP HP 55 and HPMC AS MF prolong supersaturation by increasing media viscosity and interaction with LAP are attributing for the inhibiting behaviour against crystallization.

CONCLUSION:

As an increasing proportion of drugs undergoing development are poorly water-soluble, solubilization technologies have become an essential feature in bringing them successfully to market. The solid dispersion is one such technology which in recent years has led to the approval of a large number of products, suggesting it is now the preferred technology for drug solubilization. These results emphasize that mechanisms of supersaturation could differ significantly depending on the specific drug-polymer combination. Therefore, in the designing of the solid dispersions mere selection of polymer is not important but also the maintenance of supersaturation is highly essential to get intended therapeutic effectiveness.

ACKNOWLEDGMENT:

The authors would like to thank Mr. Nannapaneni Venkaiah Chowdary, Chairman cum Managing Director, Natco Pharma Limited, Hyderabad, India for permitting the research work and utilizing the full-fledged facility.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

REFERENCES:

1. Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs. J Control Release. 2008; 129: 1–10.

2. Lipinski CA. Drug like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods. 2000; 44: 235- 249.

3. Leuner C. Improving drug solubility for oral delivery using solid dispersions. European Journal of Pharmaceutics and Biopharmaceutics. 2000; 50(1): 47–60.

4. Jain S, Patel N, Lin S. Solubility and dissolution enhancement strategies: current understanding and recent trends. Drug Dev Ind Pharm. 2015; 41: 875-887.

5. Douroumis D, Fahr A. Drug Delivery Strategies for Poorly Water Soluble Drugs. Advances in Pharmaceutical Technology. Wiley Publication, UK. 2013.

6. William R, Watts A, Miller D. Formulating Poorly Water Soluble Drugs. AAPS Advances in Pharmaceutical Science Series III. Springer Publication, NY. 2012.

7. Kaushal AM, Gupta P, Bansal AK. Amorphous drug delivery systems: molecular aspects, design, and performance. Crit Rev Ther Drug Carr Sys. 2004; 21(3):133–193.

8. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001; 48: 27–42.

9. Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Solubility advantage of amorphous pharmaceuticals: II. Application of quantitative thermodynamic relationships for prediction of solubility enhancement in structurally diverse insoluble pharmaceuticals. Pharm Res. 2010; 27: 2704-14.

10. Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997; 86: 1–12.

11. Baghel S, Cathcart H, O'Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016; 105: 2527–44.

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

13. Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharm Res. 2006; 23: 2417–26.

14. Rumondor AC, Ivanisevic I, Bates S, Alonzo DE, Taylor LS. Evaluation of drug-polymer miscibility in amorphous solid dispersion systems. Pharm Res. 2009; 26: 2523–34.

15. Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995; 12: 799–806.

16. Liu R. Water insoluble drug formulation. CRC Press, Taylor & Francis group, New York, USA. 2008. pp. 133-467.

17. Sinha S, Baboota S, Ali M, Kumar A, Ali J. Solid Dispersion: An alternative technique for bioavailability enhancement of poorly soluble drugs. Journal of Dispersion Science and Technology, 2009; 30: 1458–73.

18. Durga Maheswari Parvataneni, Mitrabhanu Mohanty, Venkata Satyanarayana Appadwedula et al. Pharmaceutical compositions comprising phenylaminopyrimidine derivative. WO2017103941 A1 2017.

19. Higa G M and Abraham J. Lapatinib in the treatment of breast cancer. Expert review of anticancer therapy, 2007; 7 (9): 1183–1192.

20. Geyer C E, Forster J, Lindquist D et al., Lapatinib plus capecitabine for HER2-positive advanced breast cancer, New England Journal of Medicine, 2006; 355 (26): 2733–2743.

21. Johnston S, Pippen J. Jr., Pivot X. et al., Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Journal of Clinical Oncology, 2009; 27 (33), 5538–5546.

22. Burris III H A, Taylor C. W, Jones S. F. et al., A phase I and pharmacokinetic study of oral lapatinib administered once or twice daily in patients with solid malignancies. Clinical Cancer Research, 2009; 15(21), 6702–6708.

23. Devriese L A, Koch K. M, Mergui-Roelvink M. et al. Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours. Investigational New Drugs, 2014; 32 (3): 481–488.

24. Koch K. M, Im Y.H, Kim S.B. et al., Effects of esomeprazole on the pharmacokinetics of lapatinib in breast cancer patients, Clinical Pharmacology in Drug Development. 2013; 2(4), 336–341.

25. Maniruzzaman M, Morgan DJ, Mendham AP, Pang J, Snowden MJ, Douroumis D. Int. J. Pharm. 2013; 443(1–2):199–208.

26. Mohanty Mitrabhanu et al. Novel techniques to prepare solid dispersions to improve solubility of bosentan. J Pharm Res, 2017; 6(12): 215-224.

27. Moore JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharmaceutical Technology. 1996; 20: 64-74.

28. Craig DQM. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002; 231: 131-144.

29. Ford JL. The current status of solid dispersions. Pharm Acta Helv. 1986; 61: 69–88.

30. Gauzman HR, Tawa M, Zhang Z, Ratanabanangkoon P, Shaw P, Gardner CR, et al. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J Pharm Sci. 2009; 96:2686–702.

31. Chauhan H, Hui-Gu C, Atef E. Correlating the behavior of polymers in solution as precipitation inhibitor to its amorphous stabilization ability in solid dispersions. J Pharm Sci. 2013; 102: 1924–35.

32. Usui F, Maeda K, Kusai A, Nishimura K, Keiji Y. Inhibitory effects of water-soluble polymers on precipitation of RS-8359. Int J Pharm. 1997; 154: 59–66.

33. Raghavan SL, Trividic A, Davis AF, Hadgraft J. Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm. 2001; 212: 213–21.

34. Simonelli AP, Mehta SC, Higuchi WI. Inhibition of sulfathiazole crystal growth by polyvinylpyrrolidone. J Pharm Sci. 1970; 59: 633-38.

35. Ziller KH, Rupprecht H. Control of crystal growth in drug suspensions. Drug Dev Ind Pharm. 1988; 14: 2341-70.

36. Bevernage J, Forier T, Brouwers J, Tack J, Annaert P, Augustijns P. Excipient-mediated supersaturation stabilization in human intestinal fluids. Mol Pharm. 2011; 8: 564–70.

37. Gao P, Akrami A, Alvarez F, Hu J, Li L, Ma C, et al. Characterization and optimization of AMG-517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J Pharm Sci. 2009; 98: 516–28.

38. Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev Ind Pharm. 2008; 34: 890–902.

39. Balani PN, Wong SY, Ng WK, Widjaja E, Tan RB, Chan SY. Influence of polymer content on stabilizing milled amorphous salbutamol sulphate. Int J Pharm. 2010; 391 :125–36.

40. Xie S, Poornachary SK, Chow PS, Tan RB. Direct precipitation of micron-size salbutamol sulfate: new insights into the action of surfactants and polymeric additives. Cryst Growth Des. 2010; 10: 3363–71.

41. Yani Y, Chow PS, Tan RB. Molecular simulation study of the effect of various additives on salbutamol sulfate crystal habit. Mol Pharm. 2011; 8: 1910–8.

42. Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Maintaining supersaturation in aqueous drug solutions: impact of different polymers on induction times. Cryst Growth Des 2012; 13: 740–51.

43. Tian F, Saville DJ, Gordon KC, Strachan CJ, Zeitler JA, Sandler N, et al. The influence of various excipients on the conversion kinetics of carbamazepine polymorphs in aqueous suspension. J Pharm Pharmacol. 2007; 59: 193–201.

44. Dai WG, Dong LC, Li S, Deng ZY. Combination of pluronic/vitamin E TPGS as a potential inhibitor of drug precipitation. Int J Pharm 2008; 355: 31–7.

45. Douroumis D, Fahr A. Stable carbamazepine colloidal systems using the cosolvent technique. Eur J Pharm Sci. 2007; 30: 367-74.

46. Zimmermann A, Millqvist-Fureby A, Elema MR, Hansen T, Müllertz A, Hovgaard L. Adsorption of pharmaceutical excipients onto microcrystals of siramesine hydrochloride: effects on physicochemical properties. Eur J Pharm Biopharm. 2009; 71: 109–16.

47. Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Understanding polymer properties important for crystal growth inhibition: impact of chemically diverse polymers on solution crystal growth of ritonavir. Cryst Growth Des. 2012; 12: 3133–43.

48. Kramarenko EY, Winkler RG, Khalatur PG, Khokhlov AR, Reineker P. Molecular dynamics simulation study of adsorption of polymer chains with variable degree of rigidity. I: static properties. J Chem Phys. 1996; 104: 4806–13.

49. Friesen DT, Shanker R, Crew M, Smithey DT, Curatolo WJ, Nightingale JA. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm. 2008; 5: 1003–19.

50. Akiyama Y, Yoshioka M, Horibe H, Hirai S, Kitamori N, Toguchi H. pH- independent controlled-release microspheres using polyglycerol ester-fatty acids. J Pharm Sci. 1994; 83: 1600–1607.

Received on 17.12.2018 Modified on 21.01.2019

Research J. Pharm. and Tech. 2019; 12(4):1664-1674.

DOI: 10.5958/0974-360X.2019.00279.8

Dissolution medium	f₁					f₂
Dissolution medium	LAP	LCPE3	LCPP3	LCPL3	LCPAS3	LAP	LCPE3	LCPP3	LCPL3	LCPAS3
0.1 N HCl	98.18	90.58	53.80	22.56	25.51	8.20	9.54	19.84	39.28	37.09
pH 6.8 phosphate buffer	98.65	93.61	66.59	0.75	1.48	6.84	7.83	15.84	95.81	87.03
	LAP	LHME3	LHMP3	LHML3	LHMAS3	LAP	LHME3	LHMP3	LHML3	LHMAS3
0.1 N HCl	98.60	87.95	87.45	12.80	10.78	2.88	5.34	5.32	41.01	45.18
pH 6.8 phosphate buffer	98.82	91.97	66.93	2.69	1.61	4.48	5.99	13.31	74.68	89.80
	LAP	LNPE3	LNPP3	LNPL3	LNPAS3	LAP	LNPE3	LNPP3	LNPL3	LNPAS3
0.1 N HCl	97.60	88.50	83.06	33.50	23.88	14.04	15.72	16.98	33.81	41.14
pH 6.8 phosphate buffer	98.41	93.61	60.90	5.98	1.45	10.06	11.12	19.21	65.75	93.12
	LAP	LSDE3	LSDP3	LSDL3	LSDAS3	LAP	LSDE3	LSDP3	LSDL3	LSDAS3
0.1 N HCl	98.32	86.80	85.98	23.38	21.09	6.30	8.91	9.03	35.05	36.28
pH 6.8 phosphate buffer	98.84	91.41	77.51	28.18	10.60	3.82	5.44	9.11	30.04	46.97