INTRODUCTION:

Poorly water soluble active pharmaceutical ingredients (API) illustrate solubility and dissolution related bioavailability problems. Drugs with low aqueous solubility undergo from poor oral bioavailability. The solid dispersion advent has been extensively used to upsurge the solubility, dissolution rate, and thereupon the bioavailability of poorly water soluble drugs. Solid dispersion is defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting, solvent, or melting solvent method¹.

The release mechanism of drug from variety of solid dispersions depends upon the physical properties of carriers as well as drug substance and preparation method used. There are number of carriers used in the preparation of solid dispersion like acids, sugars, polymeric materials, surfactants².

Lovastatin is an antihyperlipidimic drug, which inhibits the production of cholesterol in the liver. It is an inactive lactone, and hydrolyzed to the corresponding β-hydroxy acid form, which are a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. Chemically identified as [1S-[1a(R*), 3a, 7b; 8b(2S*, 4S*), 8ab]] -1,2,3,7,8,8a- hexahydro-3, 7-dimethyl-8 -[2- (tetrahydro-4 -hydroxy-6-oxo-2H-pyran-2-ylethyl]-1-naphthalenyl 2-methylbutanoate³. It is also given prophylactically for both primary and secondary prevention of ischemic heart diseases. It is a highly lipophilic drug (log P = 4.3) and it exhibeted poor oral F (less than 5%) because of its poor solubility⁴. It meets with and undergoes appreciable first-pass metabolism; hepatic extraction leads to low and variable availability of the drug to the general circulation. The very poor aqueous solubility of Lovastatin give rise to problems in the design of formulation and this led to variable oral bioavailability. Based on the above physicochemical properties, lovastatin was selected as a drug candidate for improving its solubility and bioavailability by increasing the dissolution rates. Lipid carriers such as polyglycolized glycerides (Gelucire 44/14) and PEG 6000 have been used for the preparation of solid dispersion⁵to improve the solubility of lovastatin. The solid dispersion exhibiting highest solubility and dissolution rate will be formulated into an immediate release tablet by direct compression method using cross caramellose sodium as superdisintegrant.

MATERIALS AND METHODS:

Materials:

Lovastatin was obtained as a gratis sample from M/S yarrow chem, Mumbai. Gelucire 44/14 was a gift sample from Gattefosse India Ltd, Mumbai. PEG 6000 were procured from yarrow chem, Mumbai. Neusilin US2 was obtained as gift sample from Gangwal Chemicals, Mumbai. All other chemicals and reagents used were of analytical grade.

Methods:

Phase solubility Study:

Phase solubility studies were carried through as per method illustrated by Higuchi et al⁶. An excess amount of powdered lovastatin was arranged in a screw-cap glass vial containing 20 mL of distilled water in various concentrations (0, 2, 4, 6, 8 and 10% w/v) of gelucire 44/14 and PEG 6000 (0, 2, 4, 6, 8 and 10% w/v) (Table 1). The samples were shaken at 37±0.5°C for 72h on a Remi mini rotary shaker-12R-DX. After 72h of quavering, the samples were filtered through a 0.45μm membrane filter (Auroco, Thailand). The filtrate was diluted appropriately and interpreted in an UV-Vis spectrophotometer UV-1800 (Shimadzu, Japan) at 238 nm.

The value of the apparent stability constant, for lovastatin-gelucire 44/14 and lovastatin-PEG6000 combinations was computed from the phase-solubility profiles, as described by

Ks = ^Slope/_{Intercept (1 – Slope)} (1)

The Gibb’s free energy of transfer () of lovastatin from distilled water to solutions of carrier was calculated by using formula:

(2)

Where S₀/S_sis the ratio of the molar solubility of lovastatin in distilled water of gelucire 44/14 and PEG 6000 to that in the same medium. The phase solubility diagrams are shown in Figure 1.

FT-IR spectroscopy study:

Lovastatin-carriers (1:1) interactions were evaluated by FT-IR spectroscopy (IR-Affinity-1, Shimadzu, Japan). FT-IR spectra of pure drug lovastatin and its 1:1 physical mixture with gelucire 44/14 and PEG 6000 were inscribed on IR using KBr discs. The instrument was operated under dry air purge and the scans were congregated at a scanning speed of 2 mm/sec with resolution of 4 cm^-1 over the region 4000-400 cm^-1. The FT-IR spectra are shown in Figure 2.

Differential scanning calorimetry (DSC) study:

The DSC computation were performed on a DSC with thermal analyzer (DSC-60, Shimadzu, Japan). All the exactly weighed samples (about 2 mg) were placed in sealed aluminum pans before heating under nitrogen flow (20 mL/min) at a scanning rate of 10°C/min from 25 to 175°C. An empty aluminum pan was used as reference. DSC computations were carried through for lovastatin and its 1:1 physical mixture with gelucire 44/14 and PEG6000 to study drug carrier interaction. The results are shown in Figure 3.

Formulation:

Preparation of physical mixture of lovastatin:

The drug and the carriers (PEG6000, gelucire 44/14 and neucilin US2) were weighed appropriately to the specified drug: carrier ratio (Table 2). The physical mixtures were contrived by geometrical mixing of the drug and carrier in a mortar using a stainless steel spatula. Solid mass was pulverized and passed through sieve no: 40 to get uniform sized particles. Batch size of each formulation was 50g.

Preparation of solid dispersions of lovastatin by fusion method:

Solid dispersions were formulated by fusion method^7,8. Lovastatin was combining to the melt of gelucire 44/14 and PEG6000 separately controlled at a temperature of 50^oC to obtain a clear molten mixture. The molten mixture was then supplement drop-wise to neucilin US2 with continued mixing. The solid dispersions were avowed to cool to room temperature by air-cooling followed by sieving through mesh 40. The contents and composition of solid dispersions are shown in Table 3. Batch size of each formulation was 50g.

Characterization of Formulations:

Percentage Yield:

Percentage factual yield was calculated to know about percent yield or efficiency of any method, thus it helps in excerpt of appropriate method of production. Physical mixtures, solid dispersions of fusion method were collected and weighed to determine practical yield (PY). The results are shown in table 4.

Drug Content:

The prepared solid dispersions are tested for drug content uniformity⁹. An amount equivalent to 10mg of lovastatin for each formulation was calculated, weighed and blended in phosphate buffer pH 6.8, sonicated for 10 min, filtered, diluted with same solvent and analyzed for drug content. The results are conferred in table4.

Solubility measurement:

Solubility of lovastatin, physical mixtures and its solid dispersions was determined by using flask shaker method. An excess amount of Lovastatin, and its different dispersions were introduced separately into the bottles with 25ml capacity, each containing 20ml of deionized water (pH 7.0+ 0.1)¹⁰ with uninterrupted shaking on a Remi mini rotary shaker-12R-DX at 25 ± 0.5°C for 24h to achieve equilibrium. The filtered solutions were appropriately diluted and analyzed spectrophotometrically. The results are shown in Table 4.

Flowability and compressibility measurement:

Lovastatin, physical mixtures and solid dispersions were characterized for flow and compressibility by measuring Compressibility index (%), Hausner’s ratio (H.R) and angle of repose (Ɵ)¹¹. The results are shown in Table 5.

The Hausner’s ratio is a number that is correlated to the flowability of powder. The Hausner’s ratio is determined by following formula.

Tapped Density

Hausner’ s Ratio = ----------------------- (3)

Bulk Density

Compressibility index (CI) was determined according to the formula

(Tapped Density – Bulk Density)

C.I = --------------------------------------------- × 100 (4)

Tapped Density

Angle of repose was determined by avowing the solid dispersions to flow through a funnel (with a 10 mm orifice diameter) and measuring the angle between the horizontal and the slope of the heap of solid dispersions. The radius (r) and height (H) of the pile were measured. Then the angle of repose (θ) was calculated using following formula.

(5)

In-vitro dissolution test:

The release of lovastatin from gelucire 44/14 and PEG6000 based physical mixtures and solid dispersions were determined using USP paddle type Dissolution Tester at 50 rpm. Dissolution was investigated using 900 mL of simulated intestinal fluid (SIF) without enzyme. The temperature was kept and maintained at 37±0.2°C. Samples each containing 5 mL were withdrawn at 10, 20, 30, 40, 50, 60 and 90min intervals, filtered through a Whatman filter of 0.45μm and replaced with an equal amount of fresh dissolution medium to maintain sink condition. Samples were then appropriately and suitably diluted and analyzed spectrophotometrically at 238 nm. The dissolution studies were conducted in triplicate. The results are shown in Figure 4. The dissolution profiles were investigated and evaluated for amount of drug released in initial 30 min (Q₃₀ min) and T₅₀i.e. time taken for dissolution of 50% of lovastatin.

Dissolution Efficiency:

The percent dissolution efficiency (% DE) was figured out and computed to compare the relative performance of various formulations. The % DE of a pharmaceutical dosage form is defined as the area under the dissolution curve up to a certain time, t, expressed as a percentage of the area of the rectangle described by 100% dissolution at the same time¹².The % DEcan be calculated from the following equation

(6)

Where, Y is the percent drug dissolved at time t.

Mean Dissolution Time:

To understand the extent of lovastatin dissolution rate enhancement from its formulations, the dissolution computed data were used to calculate the mean dissolution time (MDT)¹³. The MDT can be calculated by using following equation.

(7)

Where, i the dissolution sample number, n is the number of dissolution sampling times, T _mid is the midpoint between times T_iand T_i₋₁, and ΔM is the amount of lovastatin dissolved between times T_iand T_i₋₁.

Hixson Crowell Cube root law:

Finally Hixson and Crowell’s cubic root law of dissolution was practiced and applied to evaluate the effect of change in surface area on dissolution rate of all the formulations. The dissolution data of lovastatin were analyzed as per Hixson-Crowell's cube root equation. Hixson-Crowell introduced the concept of altering and changing surface area during dissolution and derived the “cube-root law” to nullify the effect of changing surface area and to straighten and linear the dissolution curves. Hixson-Crowell's cube root law is given by the following equation.

(8)

Where is initial mass and is the mass remained at time 't’, is Hixson Crowell cube root constant. All the above mentioned dissolution related parameters like Q_30,T_50,DE_30,MDT and Hixson Crowell cube root constant are summarized in table 6.

Preparation of Lovastatin Immediate Release (IR) Tablet:

The solid dispersion demonstrates highest solubility and dissolution rate was comixed with super disintegrate cross caramellose sodium and lactose. The formulation was then compressed on a 16- station single rotary tableting press (Type – CMD3 – 16. Cadmach Machinery Pvt. Ltd., Ahamadabad) using an 8-mm standard flat punch by direct compression technique¹⁴to produce lovastatin IR tablets containing equivalent of 20 mg of lovastatin (SD) product. The composition is shown in Table 7. Prepared tablets were evaluated for hardness, friability (Roche Friabilator), weight variation, and drug content. In vitro dissolution study etc.

Quality Control tests for Lovastatin IR tablets.:

The prepared tablets were subjected to standard quality control tests. Weight variation was determined by weighing 20 tablets individually, the average weight was calculated and the percentage variation of each tablet was resolute. Hardness was resolute by testing 6 tablets from each formulation using a Electrolab digital portable hardness tester EH-01 (Electrolab, India) and the average applied pressure (kg/cm²) required to crush each tablet was determined. Friability was resolute by firstly weighing 10 tablets then placing them in a friability tester EF-2W (Electrolab, India). Ten preweighed tablets were rotated at 25 rpm for 4 minutes. The tablets were then reweighed after removal of fines (using no. 60 mesh screen), and the percentage of friability was computed and calculated.¹⁵. The disintegration time for the tablets was determined in 900 mL of distilled water using a programmable tablet disintegration tester ED-2L (Electrolab, India). The results of QC test are shown in Table 8.

In-vitro dissolution test for Lovastatin immediate release (IR) tablets:

The deliverance of lovastatin from gelucire 44/14 based IR tablets was resolute adopting USP paddle type Dissolution Tester at 50 rpm. Dissolution was investigated using 900 mL of simulated and imitated intestinal fluid (SIF) without enzyme. The temperature was maintained at 37 ± 0.2°C. Tests each containing 5 mL were pulled back at 10, 20, 30, 40, 50, 60 and 90 min interims, separated through a Whatman channel of 0.45 μm and supplanted with an equivalent measure of fresh dissolution to keep up sink condition. Samples were then suitably diluted and analyzed spectrophotometrically at 238 nm. The dissolution studies were conducted in triplicate. The dissolution data and profile are shown in figure 5. The dissolution profiles were evaluated for amount of drug released in initial 30 min (Q₃₀ min) and time taken to release 50% of the drug (T₅₀). Other parameters like dissolution efficiency, Hixson Crowell cube root correlation and mean dissolution time were also evaluated (Table 9).

RESULTS AND DISCUSSION:

Phase solubility Study:

The solubility of lovastatin in water at 25°C is 0.84 mg/mL therefore it can be considered as a poorly water soluble drug. The phase solubility data for lovastatin in both the carriers PEG6000 and gelucire 44/14 are presented in table 1. From this table, it can be seen that the evident solubility of lovastatin increased with increment in the concentration of carriers. At the highest carrier concentration (10 % w/v), the solubility increased approximately 3-fold and 6fold for PEG6000 and gelucire 44/14 respectively at 25°C. A sign of the procedure of transfer of lovastatin from pure water to aqueous solution of carriers was acquired from the estimations of Gibbs free vitality change¹⁶. The obtained values of ∆G_tr^°are shown in table 1. The ∆G_tr^° values show whether the reaction condition is favorable or unfavorable for drug solubilization in the aqueous carrier solution. Negative ∆G_tr^°values indicate favorable conditions. ∆G_tr^°values were all negative for both the carriers PEG6000 and gelucire 44/14 at various concentrations, indicating the spontaneous nature of lovastatin solubilization, and decreased with an increase in carrier concentration, demonstrating that the reaction became more favorable as the concentration of carrier increased. These values also indicated that the extent of improvement in solubility was more with gelucire 44/14 as compared with PEG6000. The phase solubility plot for both the carriers showed A_Ltype solubility curve, signify that complex is formed between drug and carriers (Figure 1).

Fourier Transform Infrared (FT-IR) Spectroscopy:

The Characteristic FT-IR peaks of Lovastatin appeared at 3539.70 cm^–1 (alcohol O-H stretching), 3015.16 cm^–1 (olefinic C-H stretching), 2965.02 cm^–1(methyl C-H asymmetric stretching), 2863.77 cm^–1 (methylene C-H asymmetric stretching), 1699.94 cm^–1 (ester carbonyl stretch), 1262.18 cm^–1 (lactone C-O-C asymmetric bend), 1220.72 cm^–1 (ester C-O-C asymmetric bend), 1075.12 cm^–1 (lactone C-C symmetric bend), 1013.41 cm^–1 (ester C-O-C symmetric bend), 969.06 cm^–1 (alcohol C-OH stretch) and 870.70 cm^–1 (trisubstituted olefinic C-H). All the above peaks were also observed for the physical mixture of lovastatin with PEG6000 (1:1) and lovastatin with gelucire 44/14 (1:1). Hence there was no interaction between lovastatin and carriers used in the study. The results are shown in figure 2.

Differential Scanning Calorimetry:

DSC empowers the quantitative recognigtion of all processes in which energy is required or produced (i.e., endothermic or exothermic phase transformations). The thermal behavior of lovastatin and its physical blend with PEG6000 and gelucire 44/14 was analysed by DSC. The DSC thermogram of pure lovastatin is shown in figure 3A. The lovastatin exhibited a sharp melting peak at 169 ⁰C which uncovered that it is a pure and crystalline drug substance. The DSC thermograms of physical mixture with both the carriers are shown in figure 3B and 3C. Physical mixtures exhibited a broader peak corresponding to the combination of the carrier no peak was present associated to the melting or liquefying of the drug. We can hypothesise that during the scanning of the temperature the solid drug (when present) dissolves into the molten carrier starting from the melting of the carrier (around 45⁰C) and is no more present in its undissolved form inside the systems, when the melting temperature of lovastatin is reached.¹⁷ Hence there is no interaction between the carriers and lovastatin used in the present research.

In order to achieve improvement in solubility and dissolution rate physical mixtures and solid dispersions were readied and prepared utilizing PEG6000 and gelucire 44/14 in various drugs to carrier ratios such as 1:1. 1:3, 1:5 and 1:7. The composition of physical mixtures and solid dispersions by fusion method are shown in Table 2 and 3 respectively.

Figure 3: DSC thermograms of Lovastatin (3A) and its physical mixtures (1:1) with PEG6000 (3B) and Gelucire 44/14 (3C).

Table 2. Composition of physical mixtures of Lovastatin

Formulation Code	Lovastatin	PEG 6000	Gelucire 44/14
F1	1	1	-
F2	1	3	-
F3	1	5	-
F4	1	7	-
F5	1	-	1
F6	1	-	3
F7	1	-	5
F8	1	-	7

Table 3. Composition of solid dispersions of Lovastatin by fusion method

Formulation Code	Lovastatin	PEG 6000	Gelucire 44/14	Neusilin US2
F9	1	1	-	0.5
F10	1	3	-	1.5
F11	1	5	-	2.5
F12	1	7	-	3.5
F13	1	-	1	0.5
F14	1	-	3	1.5
F15	1	-	5	2.5
F16	1	-	7	3.5

Practical Yield and Drug Content:

The practical yield and drug content of physical mixtures and solid dispersions by fusion method are shown in table 4. It was noticed that more than 99% practical yield observed for physical mixtures whereas more than 93% practical yield was observed for solid dispersions prepared by fusion method. Drug content was high for all the formulation demonstating uniform blending and mixing of drug with carriers.

Solubility Study:

Solubility of pure drug lovastatin, physical mixtures, and its solid dispersions with various carriers were determined and presented in table 4. From the solubility study, we can gather the inference that physical mixtures with both the carriers did not demonstrate any significant change or improvement in solubility. As the proportion of hydrophilic carrier increased solubility of lovastatin also increased in solid dispersions. In case of solid dispersions with PEG6000 and gelucire 44/ improvement in solubility were 8 and 15 times respectively with the highest ratio of drug to carrier (1:7). The improved solubility of lovastatin in solid dispersions can be clarified by the enhanced wettability of the lovastatin particles in aqueous solution from both the carriers¹⁸. Improvement in solubility was more significant with gelucire 44/14 compared to PEG 6000. This might be credited to higher extent of wettability.

Table 4. Practical yield, Drug Content and solubility of physical mixtures and solid dispersions

Formulations	Practical Yield (%)*	Drug Content (%)*	*Solubility (µg/mL)**
Lovastatin	-	-	810 ± 4
F1	99.1 ± 2.2	98.5 ± 1.3	820 ± 7
F2	99.5 ± 1.5	99.2 ± 0.8	834 ± 3
F3	99.7 ± 1.3	97.2 ± 1.2	840 ± 4
F4	99.2 ± 2.3	97.1 ± 2.3	835 ± 2
F5	99.4 ± 2.1	97.3 ± 1.3	834 ± 3
F6	99.5 ± 1.3	98.1 ± 0.5	841 ± 2
F7	99.3 ± 2.1	97.3 ± 2.1	842 ± 3
F8	99.2 ± 1.5	98.9 ± 1.2	841 ± 3
F9	93.4 ± 1.9	98.2 ± 0.8	1608 ± 15
F10	94.4 ± 2.5	99.7 ± 0.5	2406 ± 13
F11	95.5 ± 2.1	98.8 ± 1.3	4907 ± 14
F12	94.5 ± 2.5	97.7 ± 2.1	5842 ± 13
F13	96.4 ± 1.2	98.6 ± 1.4	3569 ± 14
F14	95.5 ± 1.8	97.5 ± 0.9	7351 ± 16
F15	94.6 ± 3.2	984 ± 1.7	9405 ± 18
F16	95.5 ± 1.5	99.5 ± 1.2	11768 ± 12

*Mean ± SD, n = 6,

Flowability and compressibility:

The values of angle of repose, Carr’s index (C.I) and Hausner’s ratio (H.R) for drug powder lovastatin reveals that it is a poorly flowable drug. All the physical mixtures and solid dispersions showed significant enhancement in flowability and compressibility suggesting their appropriateness for tablet formulation. Some trial soild dispersions prepared without neusilin US2 showed stickiness (fusion method). Addition of Neusilin US2 (50% of the quantity of carriers) in those formulations was observed to be ideal and optimal for converting the waxy dispersion into flowable powder. These powder formulations could be prepared into a tablet. This was credited to the high oil adsorption capacity and high specific surface area of neusilin US2¹⁹. The flowability and compressibility data are shown in table 5.

Table 5. Micromeritic properties of lovastatin and its physical mixtures and solid dispersions

Formulations	Angle of Repose (⁰)*	Compressibility Index (%)*	Hausner’s ratio*
Lovastatin	41 ± 3	31 ± 1.5	1.45 ± 0.4
F1	38 ± 3	28 ± 2	1.3 ± 0.3
F2	37 ± 2	28 ± 1	1.42 ±0.3
F3	35 ± 3	27 ± 1	1.32 ±0.3
F4	34 ± 4	29 ± 3	1.39 ±0.2
F5	34 ± 2	28 ± 2	1.42 ± 0.1
F6	33 ± 3	28 ± 1	1.43 ±0.1
F7	34 ± 1	29 ± 2	1.44 ±0.8
F8	32 ± 3	28 ± 2	1.41 ±0.5
F9	24 ± 2	18 ± 3	1.23 ±0.4
F10	25 ± 2	19 ± 2	1.25 ±0.3
F11	26 ± 3	17 ± 2	1.25 ±0.2
F12	26 ± 2	18 ± 1	1.24 ±0.1
F13	24 ± 3	16 ± 2	1.22 ± 0.3
F14	23 ± 2	19 ± 3	1.24 ±0.4
F15	24 ± 1	19 ± 2	1.23 ±0.5
F16	23 ± 2	19 ± 1	1.24 ±0.4

*Mean ± SD, n = 6

In-vitro Dissolution studies:

The dissolution profile of lovastatin, physical mixtures and its solid dispersion with PEG6000 and gelucire 44/14 are shown in figure 4. In vitro dissolution studies for the pure drug lovastatin showed nearly 10% drug dissolution within 90 min. This can be attributed to its poor solubility.

Physical Mixture:

The physical mixtures of lovastatin prepared with both the carriers did not show any noteworthy change or improvement in dissolution rate. This suggests that simple addition hydrophilic carriers like PEG6000 and Gelucire 44/14 in the formulation does not enhance the dissolution of the drug (figure 4A and 4B).

Fusion Method:

In case of PEG6000 based solid dispersions (F9-F12) improvement in dissolution rate was observed with increase in the ratio of carrier (Figure 4C). This can be credited to the uniform and homogenous distribution of lovastatin in the PEG6000 crust in a highly dispersed state as a result of melt in procedure. Complete homogenous inclusion of the lovastatin particles in the carrier matrix was accomplished and achieved by incorporating the drug in the melted PEG-6000 with delicate blending and mixing. Thus, when a binary system comes in contact with an aqueous dissolution medium, the hydrophilic carrier dissolves and results in precipitation of the embedded drug into fine particles, which increase the available dissolution surface²⁰. In case of formulation F9 around 13% of drug dissolved within 30 min of dissolution study but as the proportion of PEG6000 increased from 1:1 to 1:7 i.e. F12, the drug dissolved in 30 min was 50%. The dissolution data and profile of gelucire 44/14 based solid dispersions (F13-F16) are shown in figure 4D. It was observed that as the proportion of carrier increased dissolution rate increased. This can be ascribed to the absence of crystalline structure, surfactant properties and enhanced wettability of the drug particles in the form of dispersion¹⁴. Gelucire 44/14 has an HLB value of 14 and is required to solubilize the hydrophobic lovastatin in solid state. Both solid dispersion formulations F15 and F16 exhibited more than 90% drug dissolution within 30 min. However keeping in view minimum amount of carrier, formulation F15 was selected for further formulation into tablets.

The dissolution related parmeters like Q_30,T_50,% DE_30,and MDT are presented in table 6. Pure drug and all the physical mixtures could not dissolve even 35% of lovastatin during 90 min of dissolution study. Formulation F16 showed the lowest time of 17 min to dissolve 50% of drug. The dissolution effectiveness of lovastatin was very low i.e. 9.45%. Nearly 10 times improvement in DE₃₀observed for formulation F15 and F16. Lower the mean dissolution time better is the dissolution rate of a formulation. The MDT for pure drug lovastatin and physical mixtures was very high i.e. in the range of 28 to 34 min. In case of gelucire 44/14 based solid dispersion, lower MDT values of 19 and 18 min were observed for F15 and F16 respectively. These two formulations showed minimum MDT values. The correlation coefficient for Hixson crowell cube root equation was low for pure drug lovastatin and physical mixtures whereas a higher correlation was observed for solid dispersions irrespective of the carrier. This proposes that that there was a noteworthy and significant change in surface area of solid dispersions with time of dissolution study. Both F15 and F16 showed nearly similar dissolution but keeping in view minimum amount of carrier, formulation F15 was selected for further formulation into tablets.

Table 6. Dissolution related parameters for Lovastatin and its solid dispersions

Formulations	Q₃₀	T₅₀(min)	% DE₃₀	MDT (min)	Hixson crowell cube root constant (r²)
Lovastatin	9.45	*	9.1	33.18	0.876
F1	9.71	*	9.3	32.12	0.912
F2	10.18	*	9.45	30.71	0.923
F3	17.49	*	15.23	29.37	0.924
F4	10.32	*	9.43	28.23	0.935
F5	10.1	*	9.5	31.32	0.916
F6	12.17	*	11.21	30.65	0.941
F7	17.45	*	15.46	29.29	0.945
F8	19.2	*	17.54	28.81	0.951
F9	13.11	*	11.32	30.12	0.976
F10	24.47	*	20.61	27.16	0.982
F11	45.62	40	44.97	25.51	0.992
F12	50.38	30	48.16	24.90	0.997
F13	46.62	40	43.23	24.54	0.913
F14	55.38	30	51.72	23.79	0.926
F15	98.34	18	95.38	19.67	0.998
F16	99.62	17	96.21	18.76	0.996

*50 % of drug was not dissolved within 1 h of dissolution study; % DE₃₀is thepercent dissolution efficiency at 30 min, Q₃₀ Percent of drug dissolved in 30 min.

Preparation of Tablets:

The solid dispersions prepared with different carriers such as PEG6000 and gelucire 44/14 were screened for further formulation into a tablet. In case of gelucire 44/14 based solid dispersions, most astounding dissolution was noticed. As both formulation F15 and F16 exhibited more than 90 % of drug dissolution within 30 min, solid dispersion formulation F15 was selected for further formulation into tablet keeping in view the minimum quantity of carrier. Tablet formulations were prepared with different concentrations of superdisintegrant i.e. cross caramellose sodium. One formulation was compressed without superdisintegrant (F17). Cross caramellose sodium was added as a superdisintegrant in different percentages 1, 2 and 3% of total tablet weight (F18-F20). The composition of tablet is shown in table 7.

In Vitro Dissolution for Lovastatin Tablets:

The dissolution profile of tablets is shown in figure 5. Solid dispersion (F15) demontrated an excellent dissolution rate of more than 90% in 30 min. But when the same formulation was compressed into a tablet (F17) a significant decrease in dissolution rate was observed due to slower disintegration of tablets of 32 min. This led to reduced surface area to dissolution medium. The dissolution rate decreased from 90 to 30 % at 30 min. As the proportion of crosscaramellose sodium increased (F18-F20), the dissolution rate also increased. Tablet formulation (F20) demontrated more than 90% dissolution at 30 min. Tablet formulation F20 showed similar dissolution profile as that of optimized solid dispersion F15. Henceforth tablets were subjected to assessment of dissolution related parameters.

The dissolution efficiency (DE₃₀), percent drug dissolved in 30 min (Q₃₀) and time at which 50% of drug dissolved (T₅₀) were determined for optimized solid dispersion (F15) and tablets (F17 to F20). The computed values for each formulation is presented in Table 9. Tablet Formulation F15 showed very high dissolution efficiency (98%) however when the same formulation was compressed into a tablet (F17), the dissolution efficiency decreased to 29.5. Addition of crosscaramellose sodium as superdisintegrant, increased dissolution efficiency of tablet formulations. The DE₃₀ increased from 37 to 96 % at 30 min with increase in the percentage of crosscaramellose sodium from 1 to 3%. Q₃₀ values for formulation F20 showed more than 10 fold increase in dissolution rate compared to pure drug lovastatin. Similarly T₅₀ values for pure drug lovastatin could not be determined as 50% of drug was not dissolved in 90 min of dissolution study. Lowest time of T₅₀ was observed for F20 i.e. 17 min indicating higher dissolution potential of gelucire 44/14 based tablet. Correlation coefficient for Hixson Crowell’s equation was higher for solid dispersion (F15), F19 and F20 formulations suggesting that the rate of dissolution increased with increase in surface area. Henceforth the tablet formulation F20 was selected as the best formulation keeping in view the minimum amount of superdisintegrant used.

Table 9. Dissolution related parameters for Lovastatin tablets

Formulations	Q₃₀	T₅₀(min)	% DE₃₀	MDT (min)	Hixson Crowell cube root constant (r²)
Lovastatin	9.45	*	9.1	33.18	0.876
F15	98.34	18	95.38	19.67	0.998
F17	30	60	29.5	25.5	0.934
F18	39	49	37.5	23.5	0.956
F19	65	21	63.7	22.4	0.987
F20	97	17	96.3	19.12	0.992

Figure 5. Dissolution Profile of Lovastatin Immediate release Tablets

CONCLUSION:

Henceforth from the above research work, it may be concluded that gelucire 44/14 and PEG 6000 can be used to enhance and improve the dissolution of a poorly water soluble drug lovastatin. Gelucire 44/14 and PEG 6000 played a significant and convincing role in enhancement of drug solubility and dissolution. The surface adsorbent, neucilin US2 can be used to impart good flow and compressibility to solid dispersions. Presence of crosscaramellose sodium as superdisintegrant also bequeath significantly in dissolution enhancement of drug. Among the three carriers, gelucire 44/14 exhibited better solubility and dissolution enhancement potential.

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Received on 17.03.2018 Modified on 10.05.2018

Research J. Pharm. and Tech. 2019; 12(10):4963-4972.

DOI: 10.5958/0974-360X.2019.00861.8

Concentration of carrier (% w/v)	Solubility (mg/mL)		∆G_tr^°(J/mol)*
Concentration of carrier (% w/v)	PEG 6000	Gelucire 44/14	PEG 6000	Gelucire 44/14
0	0.81	0.88	0	0
2	0.95	1.8	-1.102	- 3.624
4	1.6	2.1	-1.598	-4.129
6	2.1	3.4	-2.372	-6.313
8	2.5	3.9	-2.831	-8.631
10	2.8	4.7	-3.112	-11.223

Formulation code	Hardness (Kg/cm²)*	D.T. (min)*	Friability (%)*	Weight Variation	Drug Content (%)*
F17	5.1 ± 0.31	32 ± 2	0.67	PASS	99.9 ± 1.6
F18	5.3 ± 0.16	20 ± 1	0.23	PASS	98.4 ± 2.2
F19	5.2 ± 0.29	12 ± 0. 6	0.65	PASS	99.7 ± 3.1
F20	5.7 ± 0.52	2.4 ± 0.2	0.87	PASS	97.5 ± 1.2

Formulations	Solid dispersion (F15)			Cross caramellose sodium	Lactose Monohydrate	TOTAL
Formulations	Lovastatin	Gelucire 44/14	Neusilin US2	Cross caramellose sodium	Lactose Monohydrate	TOTAL
F17	20	100	50	0	30	200 mg
F18	20	100	50	2	28	200 mg
F19	20	100	50	4	26	200 mg
F20	20	100	50	6	24	200 mg