INTRODUCTION:

Crystallo-Co-Agglomeration is the unique agglomeration method in which crystallization and agglomeration can be approved out at the same time in one single step to change crystals directly into compact round form.¹ The typical crystallo-co-agglomeration method employs three solvents: one is the substance dissolution medium; another is a medium, which partially dissolves the substance, and third is the wetting solvent for the substance.^2,3

Spherical crystallization has limitations in applications to low dose drugs and agglomerates containing two or more drugs in combination. Crystallo-co-agglomeration is a modification of spherical crystallization. In crystallo-co-agglomeration, crystallization and agglomeration are carried out simultaneously to obtain agglomerates of two or more of drugs or drugs with excipients.³The agglomerates obtained by crystallo-co-agglomeration process are mainly used as an intermediate, which are compacted into tablets. The agglomerates can be used as final dosage form in capsules. It is possible to change the concentration of excipients used in the agglomerates to obtain predictable drug release. Levofloxacin is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration. Traditionally, fixed dose tablets of levofloxacin prepared by wet granulation technique. The dose of levofloxacine (500mg) with excipient in a fixed dose formulation is very high (more than 600mg). It is also well known that during granulation, large amount of excipients are added resulting in increment of overall bulk of the tablet (more than 600mg) which may lead to patient discomfort during swallowing of the tablet. Hence in the present study, levofloxacine agglomerates were prepared using crystallo-co-agglomeration technique to improve micromeritic, compressional and mechanical properties and make them suitable for direct compression.

MATERIAL AND METHODS:

Preformulation Study:

Preformulation study of dosage form is the first and foremost step in developmental process of any drug substance. Preformulation studies are defined as a study of chemical and physical phenomenon of drug itself and with any excipient.

Melting point, partition coefficient, permeability coefficient, micromeritics properties and solubility study of the drug was carried out.^4,5,6,7

Drug - Excipients Compatibility study:

FTIR Study:

Pure drug and with individual polymers are to be undergone FTIR study, all prepared samples were analysed between scanning range from 400 to 4000 cm−1.^7,8

Differential Scanning Calorimetry (DSC)Study:

DSC examination was done utilizing a Differential Scanning Calorimeter (Model: DSC-60; Make: Shimadzu Corporation) at a warming rate of temperature 10°C every moment in the scope of 50°C to 300°C. DSC thermo grams were recorded for levofloxacin HCl and physical blend of levofloxacin HCl andexcipients.^9,10

Preparation of Agglomerates by Crystallo-Co-Agglomeration:

Livofloxacine HCl agglomerates were prepared using a two solvent system comprising dichloromethane: petroleum ether. In a beaker, mixture of levofloxacine and DCM was uniformly dispersed. This dispersion was added immediately to the dispersion containing polymer dissolved in DCM under constant stirring conditions (500rpm) kept at ambient room temperature using paddle type agitator (RemiMotors, Mumbai, RQT 124A/D) with 4 blades. This mixture added dropwise in to petroleum ether after which temperature was maintained at 0-5°C, the mixture was stirred at 800 rpm using paddle type agitator (RemiMotors, Mumbai, RQT 124A/D) for 10 minutes. The agglomerates formed were then separated by filtration and dried at room temperature. (Table 1)

Characterization Of agglomerate:

Scanning Electron Microscopy (SEM):

The surface topography and morphology of ready agglomerates were checked by SEM (PhilipsXL-30 environment, Netherland). The samples to be checked were stick on the SEM sample stab via a double-sided sticking tape. The samples climb was covered with gold (200°A) below declined pressure (0.001 torr) for 5 minutes to get better the conductivity using an ion sputtering device (PhilipsXL-30 environment, Netherland). The gold covered samples were experiential below the SEM and photomicrographs of suitable magnification (500X to5000X).¹¹

X-RAYDiffraction:

XRD study was performed to determine crystalline nature of agglomerates or changes in crystalline nature as compared to pure drug. The sample was irradiated with the monochromatized Cu Kα radiation and analysed between 2 to 50º.

Evaluation of Agglomerates

Precompression Parameter:

%Yield:The prepared agglomerates were weighed after drying and practical yield was calculated as follow.

% yield = (practical yield/theoretical yield) × 100

Estimation of drug content:

Powdered agglomerates equivalent to 50mg levofloxacin HCl was weighed and dissolved in distilled water. The dilution was carried out using 0.1N HCl, absorbance was measured on multi component mode of spectrophotometer (Shimadzu UV spectrophotometer) at 294.0nm and using o.1n HCl solution as blank. All the experiments were done in triplicate from the absorbance drug content was calculated.

Determination of Micromeritics Properties:

All micromeritics properties like B.D, T.D, H.R, C.I and Angle of Repose was estimated which was detailed described in methodology section.

Shape Factor:

Shape factor for the formulated agglomerates was designed according to the method called mass shape factor. The mass shape factor combines the mass with the projection of the granule, so it is an influential tool in analyzing shape.¹² The mass shape factor is defined

as^φmass ^{= dmass / dprojection}

Here d_projection is defined as the projected area equivalent sphere diameter (projections of particles with stable repose on a microscope slide) and d_masswas calculated.

Determination of Mean Particle Size:

Optical microscopy has been used to determine the particle size of the prepared agglomerates. The projected diameter of total of 50 agglomerates from each batch produced was measured using an eye piece micrometer, which was previously calibrated using a stage micrometer under suitable magnification.^13,14

Determination of Mechanical Properties

Crushing Strength:

Crushing strength of agglomerates was evaluated utilizing mercury cell load technique. It was carried out by utilizing a 10ml glass hypodermic syringe. The alteration includes elimination of the tip of the syringe and the crown of the plunger. The barrel was utilized as a empty support and lead tube with close fitting to the plunger. A window was cut at the lower ending of the barrel to facilitate placement of the agglomeration the base plate. Mercury was added to the plunger at the rate of g/s from a separating funnel, from a pre-set height. The total aggregate of mercury in addition that of plunger necessary to break the agglomerate was the crushingstrength.¹⁵

Determination of Compressional Properties:

Packability andCompactability:

The packability was checked by the tapped density according to Kawakita and Kuno’s equation as follows: (n/C)=(1/ab)+(n/a), Where n is the tap number, C denotes the volume reduction which can be calculated according to the equation b, 1/a defines the degree of volume reduction at the time of tapping, termed compact-ability and 1/b is a constant related to cohesion, termed cohesiveness.¹⁶C =(V_o/V_n)/V_nwhere V_o and V_n are the powder bed volumes at initial and n_th tapped state, respectively.

Solubility Study:

Solubility studies of various batches of agglomerates were carried out according to method described by Higuchi and Connors.

Preparation of Tablets by Direct Compression:

Direct compression method was selected to manufacture levofloxacin loaded orally ingested tablets.Levofloxacin HCl and excipients were weighed and these powders were mixed with together and subjected to compression. Compression of tablets was done in rotary compression tablet machine using 10mm standard concave punch. The prepared tablet of each batch was evaluated for the tablet properties.

Characterization of Tablet of Levofloxacin HCl:

PhysicalAppearance:

It mainly includes shape and size of tablet. Also, it affects texture, any embossing matter, Colour, etc.¹⁷

Weight uniformity:

20 tablets were taking and weighed independently. Thus, tablet in an Average weight was taken and calculated the percentage deviation of individual tablet from the average weight was calculate and compared through the standard limit.^18,19

Hardness test:

The crushing strength of the tablet was measured using Monsanto hardness tester. Average of 3 reading was taken and tabulated.^20,21

Thickness:

The thickness of the tablet was determined by using a screw micrometer. Three tablets from every formulation batch were tested erratically and the average reading was noted.²²

Friability test:

The friability of the tablets was determined in Roche Friabilator. 6 tablets were weighed correctly and place in the tumbling chamber and rotated at 25rpm for a period of 4 min. Tablets were taken out and again weighed. The percentage of weight loss was determined. The experiment was frequent for three times and the average was noted.²³

Disintegration Test:

Tablets are placed in tubes fit in basket filled by buffer or etc. and basket is allowed to move in upward and downward position. Now, time taken by tablet to get disintegrate is noted. Disintegration time is evaluated as per Pharmacopoeial specification. This test exhibit quality of tablet formulation.^24,25

In-vitro Dissolutiontime:

Dissolution of the tablets of every batch was taken out by USP type-II apparatus using paddleconsisted of 900 ml of buffer solution (0.1N HCL), maintained at 37+ 0.5ºC. One tablet was placed in each dissolution vessel and the rotation speed of the paddle was set at 50rpm. Sample was withdrawn at a 5, 10, 20, 30, 40, 50, 60, 90 min. The absorbance of the solution was measured using double beam spectrophotometer at 294nm for levofloxacine HCl. Percentage cumulative drug released was calculated after each time interval.²⁶

Stability Study:

In this testing, optimized batch of oral tablet of levofloxacine HCl was analysed for Storage condition (40°C±2°C and 75%RH±5%RH) condition as per ICH Q1A (R2) guideline for stability study.Samples are withdrawn from stability chamber upon stipulated time frame and analysed for Physical Appearance, drug content etc. parameters and matched with initial data.^26,27

RESULT AND DISCUSSION:

Preformulation study:

Preformulation Parameters:

Melting point and other parameters:

The result was found in range of 224°C to 228°C. Preformulation parameter like Partition coefficient was found using the shake flask method and it was found 1.836.Permeability coefficient was estimated using equation and it was found 8.31. Micromeritics properties of pure drug were estimated. Bulk density was 0.712 g/ml, tapped density was 1.304g/ml, % CI was 31.03, Hausner’sratio was 1.44, and angle of repose was 43.32 respectively.

Solubility Studies:

Solubility studies of levofloxacin HCl was done by using different solvent like petroleum ether, N, N-Dimethyl formamide, CCL₄, toluene, diethyl ether, dichloromethane, ethyl acetate, chloroform, ethanol, acetone, methanol and distilled water. Based on the solubility study we can identify Dichloromethane work as good solvent and Petroleum Ether work as bad solvent (anti-solvent).

Compatibility Data Analysis For Drug and Excipients:

Differential Scanning Calorimetry (DSC) Study:

The thermo grams of levofloxacin HCl and its physical mixture with other polymer was shown below. The melting peak of levofloxacin HCl is 225-230°C and melting peak of levofloxacin HCl in physical mixture were found at 224-235°C temperature. The nearby value for all the sample is an indicative of physicochemical stability for drug substance with polymers.

FTIR Study:

The sample object was subjected to be analyzed by Fourier Transform Infrared spectrophotometer. Pure drug, and drug with individual polymer are analyzed.

Table 2: Data of FTIR Study

Compatibility Study of Drug Along with Polymer by Using FTIR
Functional group	C=O	C-H	O‐H
Levofloxacin HCl	1740	2970	3013
Levofloxacin HCl +PVP K₃₀ (Physical mixture)	1741	2970	1809
Levofloxacin HCl+HPMC K₁₅M (Physical mixture)	1740	2970	3014
Levofloxacin HCl +PEG ₆₀₀₀(Physical mixture)	1741	2945	3010

The spectra of levofloxacin HCl along with polymer were observed, and there was no interaction was found (Table 2). So, the drug is compatible with the polymers.

Optimization of Process Parameters:

The process was optimized by studying the effect of bridging liquid temperature, stirring, and bridging liquid on the yield and properties of agglomerates.

Effect of Temperature on Yield:

The first step was to optimize the process parameters. The agglomerates were prepared using different processing temperatures ranging from 25°C to 0°C. The study reports show maximum yield was obtained in temp range between 0°C to 5°C.

Effect of Stirring (Agitation) Speed on Agglomerates:

The agglomerates were prepared at different rpm [Low (below 500), Medium (800) and High (above 1000)] to study the effect of agitation on their properties. It has been observed that at high-speed agglomerates formed, but are very fine, at medium speed agglomerates are free-flowing with good sphericity and at low speed, agglomerates formed but the shape and size were irregular.

Effect of Bridging Liquid on Agglomerates:

In the preparation of agglomerates, the drug and the polymers were dispersed in a volatile solvent. This dispersion was added dropwise into an antisolvent under standard conditions. In the preparation of agglomerates, it has been reported that the solvent system greatly influences the process of formation and properties of the agglomerates. Hence selection of a suitable solvent system was an important criterion in the formulation of agglomeration. Initially, ethyl acetate was used to prepare agglomerates, which performed the role of bridging liquid. But the agglomerates formed were very fine and irregularly shaped with poor flow characteristics. In the subsequent batches, chloroform was used as a bridging liquid. But in this case, it was noticed that the process of preparing agglomerates was time-consuming and the agglomerates formed were sticky, and irregular in shape. Hence in further trials, chloroform was replaced with dichloromethane,which is also reported to play a role as bridging liquid. In this case, the agglomerates formed were free-flowing and spherical with good micromeritic properties.Based on the results obtained, the processing temperature of 0°C to 5°C and stirring of 800 rpm were optimized for formulating the agglomerates.

Table 3 A: Data of %Yield, Drug Content, Avg. particle size (AVS) Micromeritic Properties (Shape Factor, Bulk Density, Tapped density, Carr’s Index, Hausner’s Ratio (HR), % Porosity, Angle of repose.

Formulation	% Yield	Drug Content		Avg. particle size	Shape Factor	B.D (gm/ml)	T.D (gm/ml)	% C.I	H.R	A.R
Formulation	% Yield	mg ± S.D	% Drug	Avg. particle size	Shape Factor	B.D (gm/ml)	T.D (gm/ml)	% C.I	H.R	A.R
F₀	76.27	48.49±0.468	100	28.7±0.56	1.22±0.02	1.26±0.017	1.38±0.035	8.69	1.095	40.11±0.117
F₁	95.32	46.66±0.491	98.23	35.5±1.23	1.09±0.001	1.26±0.017	1.29±0.017	2.32	1.023	10.43±0.192
F₂	96.68	44.16±0.978	98.13	28.32±0.11	1.07±0.011	1.24±0.035	1.3±0.017	4.61	1.048	10.43±0.106
F₃	92.58	45.94±0.825	96.71	42.35±0.32	1.19±0.020	1.23±0.023	1.31±0.00	6.10	1.065	26.92±0.311
F₄	95.54	43.33±1.092	96.28	37.56±0.42	1.13±0.041	1.25±0.015	1.32±0.023	5.30	1.056	37.02±0.436
F₅	93.28	46.13±0.606	97.11	62.24±0.68	1.14±0.073	1.26±0.017	1.33±0.023	5.26	1.055	22.61±0.121
F₆	94.33	43.38±1.083	96.4	56.22±0.78	1.10±0.015	1.27±0.034	1.31±0.035	3.05	1.031	37.47±0.288
F₇	95.78	45.39±0.929	95.51	46.96±0.84	1.12±0.037	1.23±0.040	1.31±0.035	6.10	1.065	16.69±0.192
F₈	95.62	43.74±1.457	97.2	39.92±0.56	1.18±0.002	1.25±0.050	1.32±0.51	5.30	1.056	24.32±0.311
F₉	93.28	45.01±1747	94.75	33.97±0.36	1.16±0.003	1.27±0.017	1.33±0.023	4.61	1.047	17.02±0.436
F10	92.82	43.16±0.795	95.91	58.32±0.35	1.27±0.002	1.28±0.03	1.33±0.023	3.75	1.039	18.36±0.111
F11	92.56	45.37±0.400	95.51	42.67±0.67	1.14±0.004	1.26±0.017	1.32±0.023	4.54	1.047	21.02±0.436
F12	94.74	43.22±1.307	96.04	39.53±0.87	1.11±0.002	1.27±0.034	1.31±0.035	3.05	1.031	25.64±0.213

Table 3 B: Data of Weight Variation (WV), Thickness (T), Hardness (H), Friability (F), In vitro disintegration time (DT) mechanical properties, Crushing strength (CS) and Post Compression Parameters

Formulation	CS (g)	Compatibility	% Porosity	Weight Variation (%)	Thickness (mm)	Hardness (Kg/cm²)	%Friability	DT (sec)
F₀	16.42	0.0225	5.0	0.39	3.26 ± 0.06	2.88 ± 0.15	1.68 ± 0.01	85
F₁	29.27	0.0134	4.5	0.42	3.28 ± 0.07	4.08 ± 0.19	0.416±0.02	68
F₂	35.74	0.0128	4.25	0.36	3.30 ± 0.02	4.11 ± 0.05	0.376±0.02	56
F₃	27.90	0.0147	3.25	0.88	3.25 ± 0.03	4.13 ± 0.21	0.345±0.01	78
F₄	30.11	0.0137	4.25	0.94	3.32 ± 0.04	4.05 ± 0.05	0.559±0.01	65
F₅	21.90	0.0154	3.75	0.76	3.34 ± 0.04	3.98 ± 0.15	0.562±0.06	75
F₆	26.01	0.0136	3.5	0.54	3.28 ± 0.08	3.93 ± 0.20	0.589±0.01	78
F₇	28.16	0.0144	3.25	0.36	3.27 ± 0.04	4.10 ± 0.11	0.432±0.05	64
F₈	27.30	0.0152	4.5	0.49	3.25 ± 0.06	4.10 ± 0.09	0.409±0.01	69
F₉	20.53	0.0162	4.0	0.54	3.29 ± 0.09	4.22 ± 0.19	0.411±0.09	72
F10	23.48	0.0139	4.25	0.59	3.31 ± 0.05	3.97 ± 0.15	0.501±0.12	79
F11	23.27	0.0142	3.75	0.67	3.26 ± 0.07	4.00 ± 0.17	0.496±0.07	62
F12	26.74	0.0158	4.25	0.81	3.28 ± 0.04	3.95 ± 0.13	0.459±0.08	66

Evaluation of Agglomerates:

Precompression Parameters:

Yield and drug content:

The prepared agglomerates of batches F1 to F12 were evaluated for drug content and percentage yield. It was found that percentage yield of F1 to F12 batches was satisfactory and in the range of 92.56% to 96.74%. The drug content of all the agglomerates ranged from 94.75% to 98.23% for levofloxacin HCl (Table 3).

Micromeritic Properties:

Micromeritic properties of agglomerates like poured density, tapped density, percentage compressibility or Carr’s index, Hausner’s ratio and angle of repose, for the formulations, F0 toF12 were determined and the results were reported, as shown in table3A.

The flowability of agglomerates was determined by three methods namely, angle of repose, Carr’s index and Hausner’s ratio. The values of angle of repose of formulations F₀-F₁₂ were in the range of 10.43° to 40.11°, indicating improved flow. Addition ofpolymers definitely showed reduction in the values of angle of repose. This decrease in the values of angle of repose indicated improvement in flow and packability of agglomerates that can be attributed to improvement of sphericity. It was found that physical mixture of drugs showed poor flow property where as formulation F₀ which did not have any polymer showed only passable flow property. On the other hand, agglomerates prepared with PVP K30 were found to exhibit excellent flow properties. Agglomerates prepared with PEG 6000 and HPMC K4M showed fair flow properties.

Shape Factor and Average Particle Size:

In general, the sphericity of the particles is described by shape factor. Many shape factors are used to describe the agglomerates. Shape and roughness are difficult properties to define and measure and a distinction should be made between shape and roughness. A shape factor is a number characterizing a shape of a particle usually it is derived from a microscopic image of the particles. However, there are many other ways of determiningshape factor. In present study, the shape factor was calculated using the mass shape factor which combines the mass (3 dimensions) with projection of granule (2 dimension) which is reported to be a powerful tool in analyzing shape. It has also been reported that values for shape factors range from zero to unity, wherein unity represents a perfect sphere.

The shape factors for the agglomerates were found to be in range of 1.07 to 1.27. From the results, it can be concluded that addition of polymers contributed to improvement in sphericity of the particles. Improvement in sphericity can be due to coating developed on the microcrystals before their binding into agglomerates, which can result in improved symmetry of packing and therefore packing. Among all the formulations, F₁ (containing 5% PVP K30), F₂ (containing 10% of PVP K30) were found to having required shape factor (Table 3A).

Mechanical Properties:

Crushing strength of agglomerates was evaluated by mercury cell load method. Based on the results obtained, it was found that agglomerates formulated with PVP K30 possessed greatest strength. Being hydrophilic, partitions in favor of bridging liquid and impart strength to the agglomerates. Crushing strength was minimal for agglomerates containing PEG 6000.The mechanical strength of agglomerates containing polymer were found to be in the order of PVP K30 > HPMC K15M > PEG 6000.

Compaction of powder is general term used to describe a situation in which materials are subjected to some level of mechanical force. The physics of compaction may bethe compression and consolidation of two-phase system due to applied force. Various batches of agglomerates were evaluated for their compatibility using kawakita’s equation, and result was obtained 0.0128 to 0.0225. Percentage porosity estimated using mercury displacement method and result was found between 3.25 to 5 (Table 3B).

Solubility Study of Agglomerate:

In case of agglomerates formulated with PVP K30 shows good result, which was obtained for solubility studies. PVP K30 being a hydrophilic polymer, resulted in increase in aqueous solubility of the drugs. PVP K30 might be preferentially located in the dichloromethane- Petroleum Ether droplet surface and being a hydrophilic polymer, polymeric chains would have been extended at the dichloromethane- Petroleum Ether interface, with only the hydroxyl group being oriented towards the dichloromethane. Increase of wettability due to adsorption of PVP K30 on the particle surface may also have contributed to increase in solubility of agglomerates formulated with PVP K30. Solubility of agglomerates are depicted in figure 1.

Post Compression Parameters:

Physical appearance: Light yellow colored, Round, SC Tablet.

Figure 1: Solubility of Agglomerate in Distilled Water

Weight Variation, Thickness, Hardness, Friability:

Agglomerates F0 to F12 were compressed into tablets and the tablets were evaluated for friability, hardness, disintegration time, thickness, and weight variation. The results of the same are tabulated in Table 3. All the results obtained were compiled to the specifications mentioned in the IP except F₀ batch.

In-vitro Dissolution Study:

In case of agglomerates containing PEG 6000 and PVP K30, the release profile of levofloxacin HCl exceeded compare to PEG 6000. This phenomenon can be explained by the fact that both PEG 6000 and PVP K30 being hydrophilic and water miscible, did not restrict the entry of dissolution fluid into the core.¹⁶ Steady drug release in both the cases proves this phenomenon. As the concentration of both the polymers increased, there was a proportional increase in the dissolution rate of both the drugs from the tablet. This process can be due to the fact that, at higher concentration of hydrophilic polymers (PEG 6000 and PVP K30) increased wettability of the drug particles may have resulted due to reduction in interfacial tension between the drug and the dissolution fluid. Agglomerates formulated with PVP K30 had better dissolution rate compared to that of agglomerates formulated with PEG 6000.

In case of agglomerates containing HPMC K15M, the release rate of the Drug was very slow followed by steep rise. Also, as the concentration of HPMC K15M increased, release rate of the drug decreased. The logic behind this observation is very simple HPMC K15M although being a high viscosity nature of polymer, has a unique tendency to swell in presence of dissolution media. Thus, when dissolution was initiated, due to swelling of the polymer, initial release was low.¹⁷ As the concentration of HPMC K15M increased, this effect was more and hence even lesser release was obtained. But after some time, as this effect minimized, there was a steep rise in the dissolution of both the drugs. When HPMC K15M use combination with PEG 6000 and PVP K30 this problem was minimized, which was shown in formulation F₇ to F₁₂ dissolution result section.

Table 4: Data of Dissolution Parameters

Formulation	Q₃₀ (min)	Q₉₀ (min)	MDT	MRT	DE
Marketed	22.69	142.48	51.3417	50.1154	0.6877
F0	21.77	137.2	43.5004	49.5576	0.6997
F1	6.88	87.321	34.4221	38.3591	0.7854
F2	2.91	57.59	18.6026	40.6785	0.8717
F3	15.88	112.06	39.9768	45.4988	0.7392
F4	21.42	110.34	42.8036	43.6628	0.7297
F5	3.72	79.83	24.0554	42.5217	0.8323
F6	8.59	89.60	35.6043	43.1917	0.7622
F7	4.41	113.56	30.6668	49.572	0.78
F8	3.84	98.01	28.8385	44.7341	0.8105
F9	3.15	103.51	26.8958	46.5789	0.8239
F10	14.9	115.85	37.3281	46.9434	0.7483
F11	4.14	86.10	26.6379	46.1317	0.8032
F12	9.42	100.45	38.8312	43.3314	0.7542

Various dissolution parameter was evaluated like Q₃₀(time required to get 30% release of drug), Q₉₀ (time required to get 30% release of drug), MDT(mean dissolution time), MRT (mean release time),DE (dissolution efficiency). For the selection of optimization batch F₂ batch shows good result for Q₃₀, Q₉₀, MDT and DE,but in case of MRT result was slightly higher compare to F₁. From the data we are concluded that F₂ batch selected as the optimized batch because apart from MRT other parameter shows good result and in case of MRT there was no significant difference was observed (table 4).

Optimized CCA Formulation:

From the all-evaluation parameter F₂ batch was considered as optimized batch for formulation of crystallo-co-agglomerate of levofloxacin HCl, because parameter like Q30 and Q90, MRT, MDT and DE improved result. Formulation having higher solubility, % yield and drug content and improved flow properties so from these all data it was concluded F2 batch worked optimized batch for crystallo-co-agglomerate of levofloxacin HCl.

Characterization of Agglomerate:

Scanning Electron Microscopy:

SEM of Optimized Batch

Figure 2: (A) Microphotograph of Optimized Batch

1. Original magnification x500. 2. Original magnification x2000. 3. Original magnification x3500. 4. Original magnification x5000

Figure 2 (B): X-RD Pattern of Drug.

Figure 2 (C): X-RD Pattern of Optimized Formulation

The photomicrographs of agglomerates are shown in Figure 2. Theagglomerates formulated with PVP K30 (Formulation 3 with 10% polymer) were larger in size. But agglomerates slightly rough surface.

X-RAY Diffraction (XRD):

Based on graphical analysis found that reduction in second X-RD pattern which concluded that up to certain level reduction in crystalline form (Figure 2B and 2C).

ACCELERATED STABILITY STUDY:

Storage condition (40°C±2°C and 75%RH±5%RH)

Table 5: Data for Accelerated Stability Study of Optimized Batch

Parameter	Initial	After 15 days	After 1 month
Physical Appearance	Light yellow coloured, Round, SC Tablet	Light yellow coloured, Round, SC Tablet	Light yellow coloured, Round, SC Tablet
Average weight(mg)	580.2±0.078	5781.1±0.071	577.4±0.038
Thickness (mm)	3.32±0.063	3.31±0.060	3.31±0.058
Hardness (kg/cm²)	4.11±0.042	4.11±0.061	4.08±0.067
Friability (%)	0.73±0.062	0.70±0.030	0.72±0.052
Disintegration Time (sec)	68±0.095	59±0.084	63±0.028
In-vitro drug release	96.3±0.062	94.2±0.082	96.5±0.067

In this testing, optimized batch of orally ingested tablet of levofloxacin HCl was analyzed for Storage condition (40°C±2°C and 75%RH±5%RH) condition as per ICH Q1A (R2) guideline for stability study. From the data obtained from stability study there are no significant change are observed in various parameter (table 5). So, we are concluded that should be stable to regard its various properties.

CONCLUSION:

From the present studies, it can be concluded that the crystallo-co-agglomeration technique is a highly efficient technique to produce directly compressible agglomerates of levofloxacin HCl. The developed by using 10% PVP K30 agglomerate were having good yield, percentage drug content and improved micromeritic and mechanical properties (compressibility, crushing strength etc.) of the drugs and possessed higher solubility profiles which in turn, improved the dissolution rates of drug. The prepared agglomerates were directly compressible due to their altered flow properties and compaction behavior. The tablet developed from spherical agglomerate of levofloxacin HCl proved successful product in term of good in-vitro drug release. Thus, the process of crystallo-co- agglomeration is likely to have a strong impact on formulation development and can be a useful tool to ensure greater precision for solid dosage forms of poorly compressible drugs.

CONFLICT OF INTEREST:

All the authors declared there is no conflict of interest.

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Received on 13.01.2021 Modified on 22.11.2021

Research J. Pharm. and Tech 2023; 16(4):1651-1658.

DOI: 10.52711/0974-360X.2023.00270

Ingredients	F₀	F₁	F₂	F₃	F₄	F₅	F₆	F₇	F₈	F₉	^F10	^F11	^F12
Levofloxacine HCl (gm)	10	10	10	10	10	10	10	10	10	10	10	10	10
PVP K309 (mg)		500	1000					250	500			250	500
HPMC K15M(mg)				500	1000			250	500	250	500
PEG 6000(mg)						500	1000			250	500	250	500