INTRODUCTION:

Spherical crystallization process is specific as “An agglomeration process that transforms crystalline drug directly into compact spherical forms for improving the Flowability, solubility and compactability”. 1986 Kawashima used the spherical crystallization method for size enlargement of drug particles. Kawashima in 1974 suggested obtaining the size enlargement of particles during the crystallization step by controlling crystal agglomeration with controlled properties. Spherical Agglomeration is the novel particle engineering technique that can transform directly the fine crystals produced in the crystallization process into a spherical shape of drugs with or without excipients from good solvent and bridging liquid by addition of a non solvent¹.

Agglomeration is a particles technology process which involves the aggregation of smaller crystals to form bigger particles. The bigger particles are important for properties such as filtration, drying, washing etc. and the end properties such as dissolution, product formation and bioavailability. Spherical crystallization is a non conventional technique better in comparison to other conventional technique used for enlargement of particle size involves simultaneous agglomeration along with crystallization with the help of bridging liquid. It is a versatile process that controls the type and the size of the crystals^2,3. This system of molecule outline of medications has now developed as one of the consuming zones of dynamic research in pharmaceutical assembling and as of late came into the lime light because of the way that gem propensity (surface, frame, size and shape) can likewise be adjusted a the crystallization procedure. In outcome of such adjustments in the gem propensity, certain micrometric properties like mass thickness, stream property, compact ability and physicochemical properties like dissolvability, disintegration rate, bioavailability and dependability can likewise be changed which at long last outcomes in enhanced tabletting. There are many advantages of Spherical Agglomeration such as Improves the solubility, Flowability and compressibility of crystalline drugs, dramatically improved for pharmaceutical process like milling, mixing and tabletting because of their excellent flow and packability. In this research work lurasidone hydrochloride selected as model drug which is from class II drug having low solubility. Aim of the study if improve solubility of drug by Spherical Agglomeration technology^4,5,6

MATERIALS AND METHOD:

Lurasidone HCl was gifted from Lincoln Pharma, Ahmedabad, India. PVPK 30 HPMC K15 M PEG4000, PEG6000, PVA, Acetone were obtained from Oxford laboratory reagent, Thane, Mumbai, SD Fine Chem. Pvt. Ltd., Mumbai, ACS chemical reagents, Ahmedabad SD Fine Chem. Pvt. Ltd., Mumbai and Astron Chemicals, Ahmedabad respectively.

Preparation of spherical agglomerates of Lurasidone HCl using Quasi-Emulsion Solvent Diffusion:

Selection of solvent/antisolvent/bridging liquid:

The solubility of Lurasidone HCl was determined in different solvents by adding 10mg of drug to 1ml of solvent with stirring and analysis was done.

Screening of process parameters:

SCA’s of Lurasidone HCl were prepared by quasi emulsion solvent diffusion method. The following procedure was followed: 250mg Lurasidone HCl was accurately weighed and dissolved in 3ml acetone. Aqueous phase was prepared by dissolving 80mg of polyvinyl pyrrolidone in distilled water. (50ml) Drug solution was added drop wise with help of syringe to the aqueous phase under continuous mechanical stirring at different rpm. Initially droplets were formed through emulsion process. After 15min, 1.0ml dichloromethane was added as a bridging liquid and complete emulsion procedure was carried out. The prepared emulsion was kept for mechanical stirring until the organic solvent was evaporated completely resulting into formation of spherical crystal agglomerates. Formed spherical crystal agglomerates was filtered through whatman filter paper and kept for complete drying. Following process parameters were screened for formulation of spherical crystal agglomerates^7,8

Agitation speed:

Agitation speed was varied at 400, 500, 600, 700, and 800rpm. Agitation time of 30 min and aqueous phase of 50ml were kept constant in all batch. The shape of agglomerates formed in all batches was observed under microscope and agitation speed which gave spherical shape of agglomerates was selected. The selected agitation speed was used for optimization of agitation time.

Agitation time:

Here all other parameters like agitation speed 700rpm and volume of aqueous phase 50ml were kept constant. Different batches were prepared with agitation time of 30, 60 and 90 min. Agitation time which gave spherical agglomerates (seen under microscope) was selected.

Aqueous phase:

Volume of aqueous phase was varied in different batches while agitation speed (700rpm) and, agitation time (60 min) were kept constant. Aqueous volume was varied at 20, 40, 60, 80 and 100ml. The spherical crystal agglomerates were weighed and % yield was calculated as following formula:

Yield = Practical yield/theoretical yield × 100

Screening of excipients:

Upon optimization of above process parameters, various excipients were screened for selection of suitable excipient for the preparation of spherical crystal agglomerates of Lurasidone HCl. Ratio of drug: excipient (PVP K30, HPMC K15 M, and PVA) was taken as 1:0.25. and Ratio for Drug: Excipient (combination polymer) taken 1:50 (PEG 4000 taken and Combination done with all three, PVP K30, HPMC K15 M, and PVA. The formulated agglomerates were evaluated for following parameters⁹.

Saturation solubility:

10mg of prepared spherical crystal agglomerates were taken and saturation solubility was accurately weighed amount of SCA equivalent to 20mg of Drug was transferred to a 50-ml beaker and further procedure was done as described in the preformulation study.

Percentage yield:

The spherical crystal agglomerates were weighed and the percentage yield was calculated using the above described equation

Drug content:

SCA equivalent to 20mg were weighed accurately and dissolved in 0.1 N HCL. The resulting solution was filtered, diluted suitably and the absorbance was measured using UV spectrophotometer at 230nm.

Optical microscopy:

Prepared spherical agglomerates were observed under microscopy for size and shape of spherical crystal agglomerates.

Factorial designs:

It is attractive to build up an adequate pharmaceutical definition in most brief conceivable time utilizing least number of worker hours and crude materials. Generally pharmaceutical definitions are produced by transforming one variable at any given moment approach. The strategy is tedious in nature and requires a considerable measure of inventive endeavours. In addition, it might be hard to build up a perfect definition utilizing this established procedure since the joint impacts of autonomous factors are not considered. It is along these lines exceptionally fundamental to comprehend the unpredictability of pharmaceutical details by utilizing built up measurable devices, for example, factorial outline. Notwithstanding the craft of definition, the system of factorial outline is a powerful strategy for demonstrating the relative hugeness of various factors and their associations.

The number of experiments required for these studies is dependent on the number of independent variables showed in table 1. The response (Yi) is measured for each trial

Y = b₀+b₁X₁+b₂X₂+b₁₂X₁X₂+b₁₁X₁₂+b₂₂X₂₂………… (1)

Where Y is the dependent variable, b₀ is the arithmetic mean response of the nine runs and bi is the estimated coefficient for the factor X_i. The main effects (X₁ and X₂) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X₁X₂) show how the response changes when two factors are simultaneously changed

Table 1: Layout of Factorial Design

3² Full Factorial Designs
Batch No.	X1 Amount of PVA		X2 Amount of PEG 4000
F1	-1		-1
F2	-1		0
F3	-1		+1
F4	0		-1
F5	0		0
F6	0		+1
F7	+1		-1
F8	+1		0
F9	+1		+1
Translation of coded level in actual limit
Independent variables	Real Value
	Low(-1)	Medium(0)		High(+1)
Amount of PVA (X₁) (%w/v)	0.80	1.00		1.20
Amount of PEG 4000 (X₂) (%w/v)	0.40	0.50		0.60

Dependent variables:

Y1- Saturation solubility

Y2- % drug dissolution

Characterization of spherical agglomerates:¹⁰

The prepared spherical agglomerates of different drugs by different processes were characterized for following parameters:

Flow Property:

Bulk density and Tapped density, Compressibility Index, Angle of Repose and Hausner ratio was measure as per process reported method.

Saturation Solubility:

Accurately weighed amount of SCA equivalent to 20mg of Drug was transferred to a 50-ml beaker. 10ml 0.1 N hydrochloric acid was added and the contents were stirred for 24 h at room temperature using magnetic stirrer. The sample was centrifuged at 5000rpm at 4°C for 15 min, supernatant was collected, and the absorbance of solution was measured at 230nm using 0.1 N hydrochloric acid as blank. The amount of drug solubilized was calculated by measuring the absorbance of the standard Lurasidone HCl solution of a known concentration.

Assay:

SCA equivalent to 20mg were weighed accurately and dissolved in 0.1 N HCL. The resulting solution was filtered, diluted suitably and the absorbance was measured using UV spectrophotometer at 230nm.

Shape and Morphology:

The shape and surface morphology of the spherical crystal agglomerates were studied using optical microscopy and scanning electron microscope (SEM), respectively. The agglomerates were observed microscopically under a digital microscope to study their shape. For studying of the surface morphology by SEM, the samples were attached to sample stubs, silver-coated, and viewed using an accelerating voltage at the magnification of ×15,000.

Particle size analysis:

The eye piece of micrometer was calibrated and the spherical crystal agglomerates were transferred on clean slide. One or two drops of water were added. The sample was dispersed uniformly with the help of a brush. The slide was placed on the stage of the microscope. The slide was focused in low magnification (10X). The presence of individual particle was observed. The size of each particle in terms of eye-piece division was measured.

Drug- excipient compatibility study using FT-IR:

FT-IR spectra of moisture free powdered sample containing spherical crystal agglomerates was analysis performed in mixture at range of 400 to 4000 cm^-1and the degree was 1.5 cm^-1using FTIR spectrophotometer.

Differential Scanning Calorimetry Study:

The differential scanning calorimetry (DSC) thermo grams of Drug and SCA form of Drug were recorded. Five milligrams of samples were scanned from 20°C to 300°C under inert nitrogen atmosphere at a heating rate of 10°C/min using a Shimadzu thermal analyzer (Shimadzu DSC-60, TA-60, Japan).

Powder X-ray Diffraction Study:

X-ray diffraction (XRD) study was performed to evaluate changes, if any, in the crystalline nature of the drug. Powder XRD analysis was performed for SCA and pure drug using an X-ray diffractometer (X’pert Pro, Analytical, Singapore). The samples were irradiated with the monochromatized CuKα radiation and analyzed between 2° and 50° theta.

Dissolution Testing:

The amount of drug dissolved from spherical agglomerates was measured at the end of 60 minutes. The sample weight equivalent to 20mg was taken for dissolution studies. Dissolution was carried out using USP Apparatus –II (Paddle apparatus). The dissolution medium used was 900ml of 0.1 N HCl at 37^oC + 0.5^oC. The paddle speed was 75rpm. At the end of 60 minutes a sample of 5ml was withdrawn and was filtered using a 0.45μm filter (Whatman filter, Germany). The absorbance of the filtrate was measured after appropriate dilution at 230nm on UV spectrophotometer using 0.1 N HCl as a blank.

Formulation of lurasidone HCl tablet:

Spherical crystal agglomerates containing equivalent to 20mg Lurasidone HCl was accurately weighed. 10.0mg of Sodium starch glycolate, 120.0mg of MCC and 4.0mg of Aerosil were weighed accurately and added to the spherical crystal agglomerates. 4.0mg of talc and 2.0mg of magnesium stearate was added to above mixture. This mixture was taken in mortar pestle and mixed properly and pass from 40# sieve. Above mixture was compacted into tablets using a single punch tablet punching machine¹¹.

Evaluation of tablet containing spherical crystal agglomerates of lurasidone HCl:¹²

Weight variation test:

The 20 tablets were selected arbitrarily from every formulation and weighed independently to check for weight variation. The following percentage deviation in weight variation is allowed. The mean SD values were calculated.

Thickness:

Thickness was measure by Vernier calliper, and results were recorded in triplicate.

Hardness:

The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in Kg/cm². Three tablets were haphazardly picked from each formulation and the mean and standard deviation values were calculated.

Friability:

The friability of tablets was determined by using Roche Friabilator. It is expressed in percentage (%). 6.5gram weight equivalent tablets were initially weighed and transferred into Friabilator. The Friabilator was operated at 25rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again. The percentage friability was then calculated by following equation.

% Friability = Initial weight-Final weight / Initial weight × 100

Drug Content:

Five tablets were randomly selected, accurately weighed and average weight per tablet calculated. The tablets were ground individually to fine powder. Accurately weighed tablet powder transferred to 100ml volumetric flask. Add 0.1 N HCl up to the spot. After few minutes the solution was filtered; rejecting first few ml of the filtrate. 1ml of filtrate was taken in a 10ml volumetric flask and diluted up to the mark with 0.1 N HCl and analysed spectrophotometrically at 230nm.

In vitro disintegration time:

The in vitro disintegration time of a tablet was determined using disintegration apparatus. Place one tablet in each of the 6 tubes of the basket. Add a disc to each tube and run the apparatus using water maintained at 37±2°C as the immersion liquid.

In vitro dissolution studies:

The amount of drug dissolved from spherical agglomerates was measured at the end of 180 minutes. Dissolution was carried out using USP Apparatus –II (Paddle apparatus). The dissolution medium used was 900ml of 0.1 N HCl at 37^oC + 0.5^oC. The paddle speed was 75rpm. At the end of 60 minutes a sample of 5ml was withdrawn and was filtered using a 0.45μm filter (Whatman filter, Germany). The absorbance of the filtrate was measured after appropriate dilution at 230nm on UV spectrophotometer Using 0.1 N HCl as a blank.

Stability Studies:

The selected batches were subjected for stability study. All the tablets were suitably packed in aluminum foil. The tablets to be stored at 40^oC/75% RH condition. At the end of 1 month, the sealed SCA tablets were opened and evaluated for different parameters.

RESULTS AND DISCUSSION:

Optimization of spherical crystal agglomerates:

Saturation solubility measurement:

The result of saturation solubility of Lurasidone HCl in 0.1 N HCl was 0.42mg/ml. It was showed poor saturation solubility of Lurasidone HCl.

Selection of good solvent and poor solvent:

The results of solubility study of Lurasidone HCl in different solvents were calculated and highest solubility was obtained in acetone (451mg/ml) while least solubility was obtained in water (0.02mg/ml). Thus acetone was selected as a good solvent and water as a poor solvent⁹.

Screening of process parameters:

Agitation speed:

The effect of agitation speed on formulation of the spherical crystal agglomerates is evaluated. It was observed that 500rpm was insufficient speed for formulation of spherical crystal agglomerates. With an increase in speed to 700rpm, spherical shape was obtained. With further increase in the speed, the quantity of irregular shaped spherical agglomerates increased and so, 700rpm was selected as optimized agitation speed and was further used for optimization of other parameters.

Agitation time:

The result of the effect of agitation time on formulation of spherical crystal agglomerates was performed. It found that 30 min was not enough time for preparation of spherical crystal agglomerates. With an increase in time up to 60 min, formation of spherical crystal agglomerates was observed. However, with further in time up to 90 min resulted in lump formation. So, 60 min of agitation time was selected for further optimization.

Aqueous volume:

The results of effect of change in aqueous volume quantity on % yield were studied. A volume of 20ml was not enough for formulation of emulsion and it resulted in large particles. As the volume of aqueous phase was increased, % yield decrease possibly due to dilution of drug in aqueous phase that results. 60ml volume of aqueous phase gave highest yield of 92% and thus, it was selected as final aqueous volume quantity.

In Similar way ravouru n, et.al optimized process parameter for spherical Crystal Agglomerates¹³.

Screening of polymers:

SCA were prepared using various polymers and evaluated for suitable polymer that gave high drug saturation solubility, yield, drug content and spherical shape. Pure drug gave 225.4μg/ml saturation solubility in water. High saturation solubility of Drug was obtained in SCA prepared using PVA (495.9μg/ml). HPMC K15 M and PVPK 30 having less saturation solubility than PVA in water. In PVPK30 alone, the shape obtained for SCA was round and aggregated while for SCA prepared using PVA spherical shape and disaggregated without lumps.

Drug Content:

Drug content of all factorial batches F1-F9 checked and results are recorded.

Particle size analysis:

Particle Size Analysis was done for all F1-F9 batches and results recorded in Table 2. Here we can see that the particle size of formulation is more than the drug particle size. This is due to the agglomeration of polymers.

Saturation Solubility:

Saturation solubility of Formulation F1-F9 batches checked and recorded in Table 2.

Table 2: Drug Content, Saturation Solubility and Particle size of F1-F9

Batch	Drug Content (%)	Average Particle size (µm)	Saturation Solubility (µg/ml)
F1	95.8 ± 0.9	401.1 ± 0.2	545.5 ± 0.7
F2	97.7 ± 0.2	412.2 ± 0.4	578.2 ± 0.9
F3	96.6 ± 0.8	394.8 ± 0.5	602.9 ± 0.5
F4	97.8 ± 0.7	584.3 ± 0.3	679.1 ± 0.1
F5	97.3 ± 0.6	514.1 ± 0.7	644.7 ± 0.4
F6	96.1 ± 0.6	532.1 ± 0.5	661.9 ± 0.8
F7	97.3 ± 0.7	404.3 ± 0.6	599.8 ± 0.1
F8	97.4 ± 0.9	510.8 ± 0.6	634.8 ± 0.5
F9	96.6 ± 0.7	540.8 ± 0.9	587.9 ± 0.6

Flow property and compressibility measurement:

Flow ability of F1 to F9 batches containing spherical crystal agglomerates were measured using different parameters viz. angle of repose, Carr’s index, Hausner’s ratio, bulk density and tapped density. Results are recorded in Table 3.

Evaluation of prepared tablets containing spherical crystal agglomerates of lurasidone HCl:

Tablets of spherical crystal agglomerates (F9) of Lurasidone HCl prepared and evaluation of various parameters done. Results are tabulated in below table 5

Table 5: Evaluations of Tablets

Evaluation Parameters	Results
Appearance	White colored round shape tablet plain on both side
Average weight (mg)	200 ± 1.6
Thickness (mm)	3.70 ± 0.5
Hardness (kg/cm²)	5.4 ± 1.3
Friability (%)	0.56 ± 0.09
Drug content (%)	99.1 ± 1.2
Disintegration Time (sec)	49 ± 7

Fig. 7: Cumulative % drug release of F9T vs marketed product

Based on above results Fig. 7, it concluded that the marketed formulation was slow as compared to F9T formulation.

Stability study:

The final formulation tablets stored in a glass beaker lined with aluminum foil and kept in a humidity chamber maintained at 40 ± 2°C and 75 ± 5% relative humidity for 1 month. The physical and chemical parameters were investigated at the end of 1 month. The stability studies were carried out on the most satisfactory formulation F9T. There was no significant difference in Drug content (99.1 ± 1.2/98.9 ± 1.7 and % Drug Release. Stability study of batch no. F9T revealed that formulated SCA tablets of Lurasidone HCl were physically and chemically stable for 1 month.

CONCLUSION:

A solvent change method was adopted for preparation of spherical agglomerates of Lurasidone HCl using Acetone as a good solvent and water as a poor solvent. Dichloromethane was added to the solution of Lurasidone HCl as Bridging liquid. Preliminary trials were taken to identify significant factors affecting formation of spherical agglomerates. A 3²full factorial design was employed to study the effect of independent variables at the three different levels on the characteristics of the product obtained. They are amount of PVA and amount of PEG 4000.Experimental trials were performed at all possible 9 combinations and the resultant product obtained was evaluated for parameters like saturation solubility, Hausner ratio, Carr’s index and amount of the drug dissolved in 60 minutes. Based on factorial design analysis, it was found that the selected factors having significant effect on % drug release and solubility. Tablets prepared by using optimized spherical crystal agglomerates of F9 batch and evaluation done. All physical parameters found within acceptable range. Further the dissolution of tablets in 60 min found more than 90% which was also compared with marketed formulation. Stability of spherical crystal agglomerates Tablets of Lurasidone HCl found stable after 1 month.

ACKNOWLEDGMENT:

The Author and co-author, thanks to Saraswati Institute of Pharmaceutical Sciences, for providing the necessary facility to accomplish the work we also humble gratitude to our colleague and non-teaching staff for their support during the work.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 14.04.2020 Modified on 17.06.2020

Research J. Pharm. and Tech 2021; 14(3):1238-1246.

DOI: 10.5958/0974-360X.2021.00220.1

Batch	Bulk density (gm/cm3)	Tapped density (gm/cm3)	Hausner’s ratio	Carr's Index (%)	Angle of Repose (q)
F1	0.263 ± 0.03	0.315 ± 0.03	1.20 ± 0.01	16.51± 0.05	21°
F2	0.255 ± 0.04	0.324 ± 0.04	1.28 ± 0.02	21.60 ± 0.03	22°
F3	0.269 ± 0.09	0.319 ± 0.03	1.19 ± 0.01	15.67 ± 0.05	20°’
F4	0.287 ± 0.07	0.324 ± 0.08	1.13 ± 0.02	11.42 ± 0.08	22°
F5	0.290 ± 0.03	0.315 ± 0.09	1.09 ± 0.08	7.94 ± 0.04	20°
F6	0.247 ± 0.07	0.308 ± 0.02	1.25 ± 0.03	19.81 ± 0.07	17°
F7	0.235 ± 0.02	0.302 ± 0.04	1.29 ± 0.02	22.19 ± 0.09	20°
F8	0.256 ± 0.05	0.311 ± 0.07	1.21 ± 0.05	17.68 ± 0.04	22°
F9	0.285 ± 0.07	0.310 ± 0.08	1.09 ± 0.01	8.06 ± 0.06	19°

Batch No.	X1 Amount of PVA	X2 Amount of PEG 4000	Y1 Saturation solubility (µg/ml)	Y2 % Drug Release at 1hr
F1	-1	-1	544.9	41.8
F2	-1	0	577.8	48.3
F3	-1	+1	603.2	42.2
F4	0	-1	678.8	60.4
F5	0	0	645.6	49.3
F6	0	+1	660.4	43.3
F7	+1	-1	598.2	56.4
F8	+1	0	633.7	48.9
F9	+1	+1	588.2	45.3