Preparation and Characterization of Different Polymorph and Formulation of Immediate Release Tablet of Mefloquine HCL

Table 1: Methods of preparation of polymorph by crystallization method

The resulting samples were characterized by differential scanning calorimetry (DSC), X-ray diffraction pattern (X-RD) and dissolution [3].

Preparation of polymorph by exposure to temperature (40⁰C) and humidity (75 % RH):

The required number of samples were placed in petri dish subjected for 1 month at 40°C temperature and 75% RH humidity. Then samples were withdrawn at 6, 13 and 30 days of time interval and finally characterized them by differential scanning calorimetry (DSC), X-ray diffraction pattern (X-RD) and dissolution. [8]

Method of preparation of immediate release tablet of mefloquine hydrochloride (Metastable polymorph).

Direct compression method for design of immediate release tablet of mefloquine hydrochloride (Metastable polymorph) is depicted in fig. 1

Figure 1: Schematics representation of direct compression technique for design of immediate release tablet of mefloquine hydrochloride (Metastable polymorph)

Formulation design

Formulation of immediate release tablet of metastable polymorph of mefloquine hydrochloride by direct compression method. (Total tablet weight =350mg) (Table 2)

Table 2: Formulation of immediate release tablet of metastable polymorph of mefloquine hydrochloride

Evaluation of mefloquine hydrochloride metastable polymorph

The polymorphs were evaluated by Differential scanning colorimetric analysis of pure drug and prepared polymorph. Mefloquine hydrochloride polymorphs were assessed for crystallinity using an X- ray diffractometer [9].

In vitro drug release studies were carried out using tablet USP XXIII dissolution test apparatus. [10-12]. The various parameters related to dissolution which was evaluated in the present work was Drug release, Cumulative percentage drug release, Cumulative percentage drug retained. [10-12]

RESULTS AND DISCUSSION

Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. In the present investigation an attempt has been made to improve the solubility and dissolution of mefloquine hydrochloride by preparing metastable polymorph and characterized them by differential scanning calorimetry (DSC), X-ray diffraction pattern (X-RD), and dissolution, after that immediate release tablet of metastable polymorph were prepared by direct compression technique. Oral drug delivery system represents one of the frontier areas of drug delivery system. Such a dosage forms are having a major advantage of patient compliance. The UV scanning of mefloquine hydrochloride was recorded using UV 1800 Shimadzu taking methanol as reagent blank which showed λmax at 283 nm.

Compatibility study:

Physical mixture of drug and excipients (Sodium starch glycollate, Microcrystalline cellulose (PH112), Aerosil, Magnesium stearate, Talc, Polyvinyl pyrrolidone K30) were exposed to accelerated stability condition at 40⁰C / 75% RH for three months and samples were analysed for infrared spectral analysis (non-tharmal), differential scanning calorimetry(thermal) and X-ray diffraction pattern (X-RD) studies. The infrared (IR) spectra of mefloquine hydrochloride exhibited principal peaks at 3235.65 cm-1(N-H Stretching), 2958.14 cm-1 (C-H Stretching), 3235.65 cm-1(-OH Stretching). The infrared (IR) spectra of mefloquine hydrochloride and all excipients exhibited principal peaks at 3274.98 cm-1(N-H Stretching), 2940.91 cm-1(C-H Stretching), 1592.01 (C=O Stretching), 3274.98 cm-1 (-OH Stretching). From the results, it was concluded that principle functional groups of mefloquine hydrochloride were found to be unaltered in the spectra of the drug-excipients physical mixture after stability testing.

The differential scanning calorimetry (DSC) thermogram of mefloquine hydrochloride showed principal peaks at 260.52⁰C, and after stress testing (at 40⁰C / 75% RH for three month) the principal peaks at 247.09⁰C. In all drug excipients blends, the melting endotherms of mefloquine hydrochloride was well preserved with little change in terms of sharpening, broadening or shifting towards a lower temperature. These minor changes in the melting endotherm of the drug may be attributed to mixing process, which lowers the purity of each component in the mixture, thus resulting in slightly lower melting points. (Table 3).

The X-ray diffraction pattern (X-RD) study were carried out for drug-excipients physical mixture to check crystalline nature and any polymorphic changes in drug substances, after stability testing it was inferred that in mefloquine hydrochloride there is a smaller number of peak and 2θ value, where as in case of mefloquine hydrochloride and excipients physical mixture there is a greater number of peak and 2θ value. Hence, it was concluded that the drug-excipients physical mixture having more crystalline nature and certain polymorphic changes than mefloquine hydrochloride (pure drug). (Table 3).

Table 3. Data obtained from compatibility study (temperature 40 oC and humidity 75 %RH for 3 months) of pure drug and excipients by differential scanning calorimetry (DSC) and X-ray diffraction pattern (X-RD).

Pre-compression parameters:

Powder ready for compression containing polymorph and various excipients were subjected for pre-compression parameters (micromeritic properties) to study the flow properties of granules, to achieve uniformity of tablet weight.

Angle of repose (θ):

The values of angle of repose were found to be in the range of 22^o10’+ 0.11 and 27^o40’ + 0.54. The formulations prepared by direct compression methods showed the angle of repose less than 300, which reveals good flow property. The data obtained for angle of repose for the formulations were tabulated (table 4).

Bulk density:

The loose bulk density and tapped bulk density for the entire formulation blend varied from 0.321 + 0.004 gm/cm3 to 0.543 + 0.006 gm/cm3. Loose bulk density (LBD) and tapped bulk density (TBD) for the blend (table 4).

Carr’s consolidation index:

The results of Carr’s consolidation index or compressibility index (%) for the entire formulation blend ranged from 12.92 + 1.10 to 26.06 + 0.57%. The directly compressible powder had shown good to excellent flow properties (table 4).

Table 4. Micromeritic properties of mefloquine HCL metastable polymorph

Formulation design of mefloquine hydrochloride polymorph.

The present study was carried out to develop metastable polymorph of mefloquine hydrochloride by different method to improve the solubility and dissolution of the drug. The metastable polymorph of mefloquine hydrochloride prepared by-

a) Crystallization from different solvent (ethanol, methanol).

b) Exposure to temperature (40^oC) and humidity (75 % RH).

c) Photostability method.

Characterization and evaluation of polymorph prepared by different method:

The prepared polymorphs were characterized by various techniques such as: Differential scanning calorimetry (DSC), X-ray diffraction pattern (X-RD) and Dissolution.

Crystallization from different solvent (ethanol, methanol): The polymorph prepared by saturation method using methanol as solvent showed differential scanning calorimetry (DSC) principle peak at 263.21⁰C (table 5). The dissolution study shows 86.14 % drug release in 160 minutes (fig 2).

The polymorph prepared by supersaturation method using ethanol: water (2:1) as solvent showed differential scanning calorimetry (DSC) principle peak at 260.42⁰C, 264.98⁰C, 291.06⁰C. (table 5). The X-ray diffraction pattern (X-RD) pattern shows principle peak at 4,6,9,10,11,12,16,17,18,19,23,27,33, (2θ value) (table 5). The dissolution study shows 93.13 % drug release in 40 minutes (fig 2).

Exposure to temperature (40⁰C) and humidity (75 % RH):

The polymorph prepared after 6 days’ time interval showed differential scanning calorimetry (DSC) principle peak at 274.41⁰C (table 5). and dissolution study shows 86.98 % drug release in 140 minutes (fig 3).

The polymorph prepared after 13 days’ time interval showed differential scanning calorimetry (DSC) principle peak at 274.77⁰C (table 5) and dissolution study shows 85.30 % drug release in 140 minutes (fig 3).

The polymorph prepared after 30 days’ time interval showed differential scanning calorimetry (DSC) principle peak at 274.28⁰C. (table 5) and dissolution study shows 87.54 % drug release in 140 minutes (fig 3).

Table 5. Data obtained by differential scanning calorimetry (DSC) and X-ray diffraction pattern (X-RD) of polymorph prepared by different method.

Figure 2: Drug release profile of mefloquine hydrochloride (pure drug) and polymorph prepared by saturation and supersaturation method.

Figure 3: Drug release profile of pure drug and polymorph prepared by exposure to temperature (400C) and humidity (75%).

Photostability Method.

The polymorph prepared by photostability method showed differential scanning calorimetry (DSC) principle peak at 260.11⁰C (table 5). The X-RD pattern shows principle peak at 3,4,5,6,7,10,11,14,17,18,21,23,25,26,29,30,31,43,44,56 (2θ value). The dissolution study shows 84.74 % drug release in 140 minutes.

The data obtained from the above technique, polymorph prepared by supersaturation method ie. ethanol: water (2:1) shows considerable decrease in melting point by differential scanning calorimetry (DSC) better crystalline nature by X-ray diffraction pattern (X-RD) (table 5) and maximum drug release profile by dissolution process ie. 93.13% in 40 minutes, (fig 2) as compared to pure drug ie 88.94 % in 330 minutes, (fig 2), Hence, it is regarded as metastable polymorph and this method is selected as optimized one and was further selected for the formulation of immediate release dosage form.

Formulation design.

The present study was carried out to develop immediate release tablet of metastable polymorph of mefloquine hydrochloride in order to improve patient compliance and also to prepare user-friendly formulation. In this case, formulation of immediate release tablets was prepared by direct compression technique. The detailed composition of formulation is given (table 2).

Characterization and evaluation of mefloquine hydrochloride immediate release tablet.

Post-compression parameters

The tablets prepared by direct compression technique were subjected for evaluation according to various official specifications and other parameters like, hardness, friability, weight variation, in-vitro disintegration time, wetting time, water absorption ratio, drug content, in- vitro dissolution studies.

Hardness

The hardness of all the tablets prepared by direct compression methods was maintained within the 2.93 + 0.02 kg/cm2 to 3.69 + 0.03 kg/cm². 

Friability test

The friability of all the tablets prepared by direct compression methods using co-grinding process was within 0.71 + 0.01% to 0.96 + 0.04%. The values were found to be within the limit (<1%), thus tablets possess good mechanical strength.

Weight variation test

All the tablets passed weight variation test as the average percentage weight variation of 20 tablets of each formulation was within the pharmacopoeial limits of 5% which provides good uniformity. The weight variation of all the tablet was found to be 345 mg to 355 mg.

Drug content

The drugs content of the tablets were found to be between 97.58 + 0.8 % to 99.72 + 0.9 % of mefloquine hydrochloride. The results were within the range and that indicated uniformity of mixing.

Wetting time

The wetting time of the tablets were found to be between 30.00 + 1.12sec. to 48.69 + 0.56 sec. Which showed that wetting process was very rapid in formulations. This may be due to ability of swelling and also capacity of water absorption and cause swelling.

Water absorption ratio

Water absorption ratio, which is important criteria for understanding the capacity of disintegrants to swell in presence of little amount of water, was calculated. It was found to be in the range of 29.92 + 2.636 to 70.11+ 1.752%. The water absorption ratio also decrease due to less swelling property.

In-vitro disintegration time

The internal structure of tablets which are having pore size distribution; water penetration into tablets and swelling of disintegrating ingredients are suggested to be the mechanism of disintegration. These formulations showed disintegration time less than 60 seconds due to wicking and swelling mechanism of super disintegrants. Another ingredient which is included in the formulations is MCC PH 112, which is also responsible for disintegration of tablet and is highly soluble in water. Which was determined as per Indian pharmacopoeial specifications for developed formulations.

In-vitro dissolution studies

Formulations were subjected for in-vitro dissolution studies using tablet dissolution tester USP XXIII. The dissolution medium 1.2 pH acidic buffer was used to study the drug release. The samples were withdrawn at different intervals of time and analysed at 283nm using UV spectrophotometer. Cumulative percentage drug release a was calculated on the basis of average amount of mefloquine hydrochloride metastable polymorph present in the respective formulations (fig 4).

Figure 4. Percentage drug release profile of mefloquine HCL metastable polymorph immediate release tablet prepared by direct compression method.

Rapid drug dissolution was noticed in formulations, which released 98.71% at the end of 40 minutes, (fig 4) as compared to pure mefloquine hydrochloride tablet, which is having release 86.14% in 330 minutes. (fig 5). The fast dissolution might be due to metastable polymorph, lowest hardness and disintegrating property of SSG and MCC (PH 112), which leads to faster water uptake hence it facilitates faster disintegration and dissolution. The plot shows cumulative percentage of mefloquine hydrochloride released as a function of time (t) for formulations prepared by direct compression method (fig 4).

Figure 5: Drug release profile of pure drug tablet and metastable polymorph tablet.