Formation of Paliperidone Cocrystals as Multi-Component Systems for the Functionality Enhancement

INTRODUCTION

Oral route of drug administration has wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular due to their advantages because of ease of administration, accurate dosage, self-medication, pain avoidance, and most importantly the patient compliance. The most popular solid dosage forms are being tablets and capsules. One important drawback of these dosage forms for some patients however is difficult to swallow.¹

Drinking water plays an important role in the swallowing of oral dosage forms. Often times people experience inconvenience in swallowing conventional tablets and capsules, when water is not available, in case of motion sickness (kinetosis) and sudden episodes of coughing during the common cold, allergic conditions, and bronchitis. For these reasons, tablets which can fast dissolve or disintegrate in the oral cavity have attracted a great deal of attention.Orodispersible or disintegrating tablets are not only indicated for people who have swallowing difficulties, but also are ideal for everyone.^2,3

 The non covalent derivatization, prevalently known as cocrystallization, is one of the approaches to alter the physicochemical properties such as solubility, dissolution, and stability without the need of covalent linkages.^4-7 The process involves homogenous mixing of the drug with coformer molecule such that they interact with each other by intermolecular interactions in a definite stoichiometric ratio to form a cocrystal lattice.^8,9Both the ingredients accommodate in such a way that no wastage is generated. For the screening of coformers and prediction of cocrystal formation, Hansen solubility parameter can be employed.^10,11

Orodispersible Tablets (ODTs) are those when put on tongue, disintegrates instantaneously, releasing the drug, which dissolves or disperses in the saliva. These dosage forms dissolve or disintegrate in oral cavity within a minute without the need of water. These are useful in administration of drugs in pediatric and geriatric patients and also in patients suffering from dysphasia, leading to improved patient compliance. Several approaches have been employed to formulate ODTs which involve the techniques like tablet molding, increasing porosity by freeze drying, sublimation, drying, disintegrants addition, and use of sugar excipients.^12,13

Paliperidone is a dopamine antagonist, belongs toBCS Class II, used as an antipsychotic drug in the treatment of acute schizophrenia, a chronic disorder which affects about 1 % of the world’s population.^14,15 There is no reported literature on the orodispersible tablets of paliperidone so far. The aim of this study was to develop and characterize ODTs of paliperidone cocrystals which rapidly dissolve in the mouth through the presence of saliva and is swallowed directly. By observing the properties of paliperidone, particularly the lower dose of paliperidone (3 mg) and the advantages of paliperidone ODTs both in adults and children, it was considered that paliperidone wasa suitable drug. 

MATERIALS AND METHODS

Chemicals:

Paliperidone drug was procured from Unimark Remedies Ltd, Vapi. Superdisintegrantssuch as SSG,CCS, and CP XL-10 were procured from ZydusCadila, Ahmedabad. Magnesium stearate and Microcrystalline Cellulose (MCC) were purchased fromLobaChemie Pvt. Ltd., Mumbai and Indchem International, Mumbai, respectively. All other chemicals used in this study were obtained from SD Fine Chem. Limited, Mumbaiandwere of analytical grade.

Preparation of cocrystals:

Cocrystals are formed by hydrogen bonding between paliperidone and coformers. The two coformers were selected from the GRAS (Generally Recognized as Safe) list namely Para HydroxyBenzoic Acid (PHBA) and Sodium Saccharin (SS). SS has one hydrogen bond donating group and three hydrogen bond accepting groups. Similarly, PHBA has two hydrogen bond donating groups and three hydrogen bond accepting groups. On the other hand, paliperidone has one hydrogen bond donating group and seven hydrogen bond accepting groups. Therefore, cocrystals may form from this combination.

Cocrystals are formed when the difference in the solubility parameter of the drug and coformer is less than 5 MPa1/2.16 The solubility parameter calculated by group contribution method using Fedors constants for PHBA (29.49 MPa1/2) and SS (27.78 MPa1/2) fall nearer to the solubility parameter of paliperidone (25.39 MPa1/2). Since the difference in the solubility parameter of the drug and the coformer was less than 5 MPa1/2, it was assumed that cocrystals would form.

Several methods are adopted to prepare cocrystals such as solvent evaporation, solid state grinding, solution crystallization, slurry conversion, melt crystallization, hot melt extrusion, and spray crystallization. Solvent evaporation technique was employed in the preparation of paliperidone cocrystals. Cocrystals were prepared by dissolving paliperidone and coformer (PHBA and SS) at 1:1 molar ratio in ethanol. The solvent was allowed for slow evaporation at room temperature. Good quality paliperidone cocrystals were grown. The surface solvent was removed by storing the sample in desiccators, containing calcium chloride in the well for 2 weeks.

Determination of melting point:

Melting point of the paliperidone and cocrystalswere determined by DBK programmable melting point apparatus using open capillary method.

Aqueous solubility studies: The solubility of paliperidone and its cocrystals were studied in distilled water. Four ml of distilled water was taken in 25 ml volumetric flasks. Paliperidone and cocrystals were added in excess separately in each volumetric flask. The volumetric flasks were rotated incryostatic constant temperature shaker bath at room temperature (25 ºC) at 75 rpm for 24 hours to obtain equilibrium. After attainment of equilibrium, aliquots were withdrawn, filtered, diluted with distilled water, and analyzed at 238.0 nm.¹⁷

Dissolution studies of paliperidone cocrystals:

Dissolution studies were conducted using USP dissolution test apparatus II (paddle type). Paliperidone and thecocrystals containing the drug equivalent to 25 mg were taken and filled in hard gelatin empty capsules. Dissolutionstudies were carried out in 900 ml of 0.1 N HCl for 60 min at 37 ± 0.5 ºC temperature and at a stirring speed of 50 rpm. Samples were withdrawn at time intervals of 10, 20, 30, 40, 50, and 60 minutes. The samples were filtered through 0.45-μm filter. Further dilutions were made and analyzed spectrophotometrically at 238.0 nm.

FTIR spectroscopy:

FTIR studies were carried out for the paliperidone and its cocrystals using Bruker Alpha FTIR, Bruker. The source provided a continuous spectrum of radiation ranging from 4000 to 500 cm-1 with a resolution of 1 cm-1.18 Intensities of absorption bands were expressed as % transmittance. Potassium bromide pellet method was employed for the sample preparation. The samples were added to the powdered potassium bromide in the ratio of 1:100. The mixture was compacted under pressure (10tons/cm2) in vacuum to form a transparent pellet (13 mm in diameter). The spectrum was obtained by placing the pellet in the IR chamber and the peak intensities were recorded.

DSC studies:

DSC studies were performed using Differential Scanning Calorimeter for paliperidone and its cocrystals. Accurately weighed samples were placed intoflat-bottomed aluminium pans, which were then sealed with perforated lids. The samples were measured over a range from 0-400 ºC.All measurements were taken under nitrogen flow (flux rate of 70 mL min−1) at a heating rate 5 °C min−1. DSC instrument was calibrated using indium and zinc as standards with respect to temperature and enthalpy.¹⁸

PXRD studies:

The cocrystals of paliperidone and pure drug were characterized at 25o C using XPERT-PRO diffractometer with Cu-Kα (λ=1.54060 Å) at 45 kV and 40 mA. Data were collected with a specimen length of 10 mm over an angular range of 4o to 50o 2 θ in a continuous scan mode using a step size of 0.0170 °2θ value and a scan speed of 1.0 min-1.19

SEM studies:

Scanning electron microscopy studies of cocrystals were carried out to study surface topography, texture, and morphology. The cocrystals were mounted using a double-sided sticking tape and coated with gold (200 Ao) on the SEM sample stab, under reduced pressure of 0.001 torr for 5 min using ion sputtering device. The gold-coated samples were observed under the scanning electron microscope(JEOL JSM 6100, Japan) at SAIF, Punjab University, Chandigarh.The sample was scanned in the instrument to get photomicrographs of suitable magnification.

Formulation of ODTs of paliperidone cocrystals:

Paliperidone tablets were manufactured for the six batches F-I to F-VI using different types of superdisintegrants, keeping the total weight (200 mg) of the tablet constant in all the formulations.Paliperidone tablets were prepared by direct compression, as per the formulae given in the Table 1, using thesuperdisintegrants such as SSG,CCS, and CP at a 5% concentration. All the ingredients were passed through sieve #40 and were subjected for drying to remove the moisture content at 40 to 45o C. Weighed amount of drug and excipients except magnesium stearate were mixed in a polybag by geometric addition method for 20 minutes manually. Magnesium stearate (Mg Stearate) was then passed through sieve #80, mixed, and blended well with the initial mixture.The mixed blend of drug and the excipients was compressed on Rimek 10 station rotary punching machine using 7 mm diameter flat faced punches.²⁰

Evaluation of pre-compression parameters:

Prior to compression of the ODTs, the powder blends were evaluated by various parameters such as tapped density and bulk density. The flow properties of powder were assessed by angle of repose and its compressibility by Carr’s index and Hausner’s ratio.^21-23

Evaluation of post-compression parameters: Dimensions:

Thickness and diameter of the tablets were measured using digimatic micrometer (Mitutuyo, Japan).The values of thickness were used to adjust the initial stages of compression.

Weight uniformity test:

Twenty tablets were weighed individually and all together. Average weight was calculated from the total weight of all the tablets.The individual weights were compared with the average weight. The percentage difference in the weight variation should be within the permissible limits (±7.5%). Any variation in the weight of tablet (for any reason) leads to either under medication or over medication. So, every tablet in each batch should have a uniform weight. Deviation within the IP permissible limit of 7.5% is allowed as the tablet weighs 200 mg.Corrections were made during the compression of tablets to get uniform weight.

Hardness test:

Hardness (diametric crushing strength) is a force required to break a tablet across the diameter.The hardness of a tablet is an indication of its strength. The tablet should be stable to mechanical stress during handling and transportation. The degree of hardness varies with the different manufacturers and with the different types of tablets.The hardness was tested using Pfizertester.“Hardness factor”, the average of the six determinations, was determined and reported.The force was measured in kilograms per centimeter square.

Friability test:

Friability is the loss of weight of tablet in the container/package, due to removal of fine particles from the surface. This in process quality control test is performed to ensure the ability of tablets to withstand the shocks during processing, handling, transportation, and shipment. Maximum allowable friability was considered to be 0.8 %. Roche friabilator (Electrolab, Mumbai) was used to measure the friability of the tablets. Ten tablets were weighed collectively and placed in the chamber of the friabilator. In the friabilator, the tablets were exposed to rolling; resulting free fall of tablets (6 inches within the chamber of the friabilator). It was rotated at a rate of 25 rpm. After 100 rotations (4 minutes), the tablets were taken out from the friabilator and intact tablets were again weighed collectively.

Content uniformity test:

One tablet was powdered and shaken with 25 ml of 0.1N HCl for 30 minutes and sufficient 0.1 NHCl was added to produce 100.0 ml and filtered. One ml of the filtrate was diluted to 10.0 ml with 0.1 N HCland the absorbance of the resulting solution was measured at 238.0 nm.

In Vitro dispersion time:

In vitro dispersion time was measured by dropping a tablet into a petridish containing 10 ml of phosphate buffer solution pH 6.8 (simulated saliva fluid). Three tablets from each formulation were randomly selected and in vitro dispersion time was found and expressed in seconds.

In Vitro drug release:

In vitro drug release of the samples was carried out using USP – type II dissolution apparatus (paddle type). The dissolution medium, 900 ml of 0.1 N HCl was placed into the dissolution flaskmaintaining the temperature of 37 ± 0.5o C and rpm of 50. One paliperidone tablet was placed in each flask of dissolution apparatus.The apparatus was allowed to run for 60 min.Samples measuring 10 ml were withdrawn after every 10, 20, 30, 40, 50, and 60 min. Samples were filtered through 10 μm filters. The fresh dissolution medium was replaced every time with the same quantity of the sample. The collected samples were analyzed at 238.0 nm using dissolution medium as blank. The cumulative percentage drug release was calculated. The test was conducted thrice and average and standard deviation values were calculated.

Stability study:

The tablet formulations were evaluated for accelerated stability conditions for a period of six months. Samples were put in screw-capped glass bottles separatelyat 40 °C /75% RH in the stability chamber (SC16 PLUS,Remi, India). At the end of the study, samples were assessed for the dissolution profiles.

RESULTS AND DISCUSSION

Melting point:

Melting points of the paliperidoneand its cocrystals determined were shown in the Table 2. Melting point of PAL-PHBA cocrystals fell between the melting points of the partners where as that of PAL-SS cocrystals fell lower than the melting points of both the partners. A statistical study on 50 cocrystal systems indicated that, majority of cocrystals (26/50, 51%) had melting points in between those of the drug and coformer, 19/50 (39%) were lower than either the drug or coformer, 2/50 (4%) had the same melting point as either the drug or coformer and only 3/50 (6%) were higher than both the drug and coformer. The precise reasons for melting point alterations are not known and are probably linked with the melting points of coformer. There was a difference in the melting point of cocrystals from that of the partners giving a clue that the change in the melting point may be attributed to the intermolecular interaction of the drug and coformers in the crystal lattice. This was further evidenced by DSC studies.

Solubility behaviour of paliperidone cocrystals: Solubility data of cocrystals in water have been obtained and are shown in the Table 2.The PAL-PHBA cocrystals showed142 times higher solubility than the pure drugwhere as PAL-SS cocrystals showed 43 times. The increase in the solubility is due to the formation of cocrystals. The increased solubility of the drug is enormous and suits for the purpose of preparing paliperidone ODTs.

Dissolution of paliperidone cocrystals: The dissolution patterns of the paliperidone and its cocrystals are shown in the Fig 1. The paliperidone cocrystals with PHBA (PAL-PHBA) have shown faster and higher release (100 % within 30 min), followed by paliperidone cocrystals with sodium saccharin (PAL-SS,94.72% at 60 min). Both the cocrystals have shown higher dissolution rate when compared to the paliperidone pure drugie., 48.84 % at 60 min. Thus increased rate of dissolution could lead to increased bioavailability.

FTIR spectroscopic analysis:

The intermolecular interactions by hydrogen bonding can be examined by FTIR spectroscopic studies. The FTIR spectrum of pure drug (Fig 2)had shown the characteristic stretching bands of C-F at 1273.06, O-H at 3292.60, C-N at 1339.61, C=O (Carbonyl) at 1627.97, C=O at 1534.42, =C-H at 3046.67, and SP3 C-H at 2934.79 cm-1. In the spectrum of PAL-PHBA cocrystals (Fig 3), the shifts were occurred in the stretching bands of C-N (1375.25), C=O (Carbonyl, 1656.85)C=O (1529.55), =C-H (3076.46), and SP3 C-H (2964.59)due to the formation of hydrogen bonding. Similarly, thespectrum of PAL-SS cocrystals (Fig 4) showed slight changes in the peaks of bands,C-F (1255.70), O-H (3336.00), C=O (Carbonyl,1646.30), C=O (1586.50), =C-H (3013.57), and SP3 C-H(2926.11). These resultsrevealed the formation of supramolecular heterosynthons. Further, these slight changes in the vibrational frequencies of the cocrystals confirm the absence of proton transfer, which occur in case of salt formation.

X- Ray Diffraction Studies:

The diffractograms of paliperidone and its cocrystals were shown in Fig 5 to 7. The peak 2θ values obtained for the pure drug(14, 24, 22, 18, and 10 with an intensity of 100, 50.66, 48.00, 33.33, and 30.66, respectively) were different from the PAL-PHBA (2θ; 13, 25, 16, and 24 with an intensity of 100, 94.32, 62.58, and 56.35,respectively) and PAL-SS (showed 2θ value2, 12, 24, and 31 at an intensity of 100, 15.78, 17.13, and 14.47, respectively). The differences in the 2θ of the cocrystals, without any presence of parental crystal phase, clearly indicate the purity of the new crystalline phase formed in the cocrystals. The presence of additionalcrystalline peaks that present in the diffractogram of the cocrystals also reveals the formation of cocrystals.

Differential scanning calorimetry studies:

The DSC thermogram obtained for paliperidone and cocrystals are shown in Fig 8 to 10. Themeltingpeak obtained for paliperidone (175.35oC) wasdifferent from melting peaks obtained from PAL-PHBA(98.77oC) and PAL-SS (126.51oC). Reduction in the melting point of the cocrystals clearly indicated the formation of new single crystalline phase that have less cohesive energydue to weak hydrogen bonding between the partners in the crystal lattice. Moreover, a remarkable difference in the heats of fusion for the drug (43.70 J/g) and cocrystals (PAL-SS; 122.36J/g, PAL-PHBA; 228.12J/g) were also clearly indicated the formation of distinct crystal lattice in cocrystals. A small peak seen in thermogram of PAL-SS at 187.41oCcould be due to the melting of unreacted paliperidone. Similar peak was also seen in thermogram of PALPHBA cocrystals, which again for the same reason. The intensities of the second peaks indicate that paliperidone requires equimolar concentration of sodium saccharin to form cocrystalsbutin case of PHBA, the coformerproportioncouldbe increased.The study revealed that the DSC method can be successfully applied in order to knowcocrystallization occurring in a mixture when heated under non-isothermal conditions.

Scanning electron microscopy: The morphological evaluation of the paliperidone and cocrystals was done using SEM analysis as shown in Fig 11 to 13. The topography studies revealed that the surface texture and shape of paliperidone pure drugis different from that of its cocrystals. Paliperidone appeared clumps of material with approximately cube shaped structure, which could be the reason for lesser solubility and dissolution profiles. Whereas the SEM images of cocrystals indicated platy shaped crystals with relatively smooth surface texture. The distinct morphology of the cocrystals with micrometer sizes represents them as separate entities from the pure drug molecule which might be resulted in the improved processing parameters.

ODTs ofpaliperidone cocrystals (F-I to F-VI):

By integrating the results of all the characterization tests, it was confirmed that cocrystals of paliperidone have been formed and are exhibiting better physicochemical properties,whichare needed to make them suitable for the manufacture of ODTs. Further it was aimed to prepare ODTs of paliperidone using superdisintegrants, which may assume to increase the dissolution profiles. Three batches of the PAL-SS formulations and three batches of PAL-PHBA formulations were prepared using 5% of superdisintegrants (CCS, SSG, and CP). The pre-compression and post-compression parameters of the six batches of paliperidone ODTswere studied.The properties of powder blend and ODTs are shown in Table 03 and Table 04, respectively. The results were encouraging as all the parameters were well within the limits.

Dissolution of the paliperidone ODTs:

The formulationsof PAL-SS (F-I toF-III) were prepared using the 5% superdisintegrants. The dissolution profiles of the tablets are compared with the dissolution of paliperidone pure drug and paliperidone cocrystals (Fig 14). All the formulations have shown complete drug dissolution within 10 minutes. The increase in the dissolution rate compared to the dissolution rate of cocrystals is attributed to the presence of superdisintegrants, which work by rapid swelling and disintegrate the tablets rapidly into apparently primary particles. Similar dissolution profiles were obtained for PAL-PHBA ODTs(F-IV to F-VI) as shown in Fig 15.Thus preliminary testing of suitability of paliperidone for the manufacture of ODTs can be considered successful and needs further investigation.

Stability study:

Physical and chemical stability study of the prepared tablet formulations was investigated for six months under accelerated conditions (40 °C /75% RH). From the statistical analysis, the dissolution profiles of prepared tablets were estimated to be similar (f2> 50) before and after study. Further, DSCand IR data of cocrystals showed all the characteristic peaks with no deviation in melting behavior as compared to fresh sample suggesting the stable nature of cocrystals. Hence, the issue of stability will not barricade the commercialization of the prepared tablets.

CONCLUSION

Cocrystallizationprovides one of the most encouragingmethods to improve physicochemical properties of drug substances. Paliperidone cocrystalswere prepared using PHBA and saccharin sodiumby solvent evaporation method. This method of laboratory scale to prepare cocrystalscan be transformed to potentially large scale continuous production method. The cocrystals, prepared using equimolar concentration of drug and coformer, were confirmed by characterization techniques such asmelting point, solubility studies, dissolution studies, FTIR, DSC, PXRD, and SEM studies.ODTs of paliperidone cocrystals efficiently and successfully formulated by employing superdisintegrant addition method to generate prima facei evidence. Detailed insight is given on the mechanism of cocrystallization and working of ODTs. The prepared tablets complied for pharmacopoeial and non-pharmacopoeialtests.It is anticipated that this data will certainly become a suitable platform for further development of paliperidone ODTs.

ACKNOWLEDGEMENT

The authors are thankful to Advance Research Wing, Rajiv Gandhi University of Health Sciences, Karnataka, for funding this research project.