INTRODUCTION:

Various approaches have been reported by several authors such as inclusion complex, solid dispersion (SD), co-solvents and nano-carriers for bioavailability enhancement by increasing solubility or enhancing dissolution rate^1,2. SD enhances the aqueous solubility by several ways such as improved wettability, amorphanization of drug and drug particle size reduction^3,4,5. Generally SD technique is applied to the immediate release formulation but sustained release oral dosage form development of SD is also a desirable approach for patient compliance improvement. However, very few studies have been reported on sustained release systems of SD due to recrystallization occurrence of drugs on longer contact of SD to water^6,7.

This longer duration contact between water and SD was more with hydrophilic release controlling polymers. A disintegration-controlled matrix tablet (DCMT) having wax matrix for reducing contact between SD and water was developed by Tanaka et al. The drug release from DCMT was controlled by slow erosion of disintegrant molecules ⁸.

Domperidone (DOM) is a weak base (pKa=7.89), practically insoluble in water, octanol to water ratio (log P) of 3.90 and bitter in taste^9,10. Clinically, DOM is potent antiemetic; antimigraine drug effective for preventing different kinds of emesis. Its conventional dosage form such astablet and suspension give poor bioavailability (18%) due to extensive first pass effect, whereas on rapid I.V. injection it has been shown to cause cardiac arrhythmias^11,12. In addition to its bitter taste, DOM needs to be taken 3-4 times a day [4]. In present work, the intention was to develop DOM-poly ethylene glycol (PEG) solid dispersion’s sustained release (SDSR) granules by treating SD with lipid, stearic acid. The developed formulations should aim to minimize the frequency of the dosing by sustained release formulations and to improve its palatability. Further therapy with geriatric patient or other patients where swallowing might be responsible for poor patient compliance, an oro-dispersible formulation is an appropriate strategy. For improving patient compliance we tried to develop oro-dispersible tablets of lipid treated SDSR granules (OD-SDSR). Lipid was included to reduce contact time between SD and water as well as for sustained drug release. Super-disintegrant was included to produce oro-dispersion inside mouth cavity for ease in swallowing.

MATERIALS AND METHODS:

Materials:

Domperidone (DOM) obtained as gift sample from Alchem Lab. Ltd, Mumbai, India. Stearic acid (SA) was purchased from Sigma-aldrich, USA. Croscarmellose sodium (Ac-Di-Sol) gift sample was obtained from Sanjivani parenteral ltd, Dehradun, India. Polyethylene glycol 4000 (PEG), magnesium stearate, dimethyl formamide, hydrochloric acid, dihydrogen ortho phosphate, sodium hydroxide were purchased from CDH Ltd, Delhi, India.

Preparation of the solid dispersions:

Solid dispersions of domperidone were prepared using melting method¹³. PEG was heated at a temperature of 70⁰C using a thermostatically controlled water bath. DOM in a 1:1, 1:2, 1:3 and 1:4 drug to polymer ratio was dispersed in the molten PEG with stirring. The resultant mixture was cooled to room temperature using an ice bath and stored for next 24 hr at 4⁰C. Finally solid product was sifted through a 60 no. mesh sieve.

Preparation of SDSR granules:

SD of DOM was treated with Stearic acid. Required amount of stearic acid was melted in petri dish at temperature just above its melting point using heating plate. Fine SD was added and dispersed into molten stearic acid with help of fused glass capillary. The molten mixture was instantly cooled with help of ice bath. After cooling solidified mass was then passed through sieve no 16 to form lipid treated granules of SD of DOM.

Preparation of Oro-dispersible tablet of SDSR granules (OD-SDSR):

SDSR granules with other excipients (Table 2) were blended in a double cone mixer for 10 min. Constant amount of Magnesium stearate (0.5%) as lubricant was added and blended for another 2 min. These granules were directly compressed using flat 10 mm punches punch on a sixteen station single rotary compression machine (Cadmach Machinery Co. Pvt. Ltd., Ahmedabad, India). The compression force was kept in such a manner to keep hardness of tablets between 30-40 N.

FT-IR study:

FT-IR spectra were obtained by a Thermonicolet NEXUS spectrometer. Samples were pressed into KBr pellets and recorded at frequencies from 4000 to 200 cm^-1.

X-ray powder diffraction (XRPD):

XRPD studies were performed using a X-ray diffractometer (X’Pert Powder PANalytical system, Netherlands) with Cu Kα radiation generated at 40 mA, 35kV. Samples were scanned in the range of 5 degree (2θ) to 50 degree (2θ).

Differential scanning calorimetry (DSC):

DSC was carried out using Perkin Elmer DSc, USA. A mass of 10mg samples were accurately weighted, sealed in an aluminium pan with nitrogen environment (Nitrogen (20ml/min)) and equilibrated at 25°C, which were subjected to a heating run over the temperature range of 25–350 ^◦C.

Evaluation of Oro-dispersible tablet properties:

Tablet Geometry:

The tablet geometry was determined by a means of a vernier’s calipers. Both thickness and diameter of tablets were recorded.

Hardness:

The hardness of ten tablets was measured using a Monsanto hardness tester.

Friability:

The friability of a sample of twenty tablets was measured using a Roche friabilator. Twenty pre-weighed tablets were rotated with speed of 25 rpm for 4 min. The tablets were then dedusted and reweighed, and the percentage of weight loss was calculated.

Drug content:

For drug content estimation, ten intact tablets (each equivalent to 50 mg of DOM) were transferred individually into clean and dry 100 mL volumetric flasks. 100 mL of 40:60 DMF and distilled water was added. Then it was allowed to cool to room temperature and volume was made up to the mark with 40:60 DMF and distilled water. After suitable dilutions samples were analyzed by UV.

Weight Variation:

Twenty tablets were selected at random and weighed individually. The average weight of twenty tablets was calculated. Individual Weights were compared with the average weight and standard deviation was calculated.

Pharmacopoeial in-vitro Disintegration test:

The test was carried out on 6 tablets using the apparatus specified in pharmacopoeia. Distilled water at 37ºC ± 2ºC was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured in seconds¹⁴.

Modified in-vitro Disintegration test:

In vitro disintegration test for ODT was determined using a relatively simple method with rigorous conditions was developed to evaluate the DT of rapidly disintegrating tablets ¹⁵. Each individual tablet was dropped into 10 mL glass test tube (1.5-cm diameter) containing 4 mL distilled water, and the time required for complete tablet disintegration was observed visually and recorded using a stopwatch. The visual inspection was enhanced by gently rotating the test tube at a 45- angle, without agitation, to distribute any tablet particles that might mask any remaining un-disintegrated portion of the tablets.

In-vitro release study:

The release study was carried out using dialysis bag of 12-15 kD cutoff. The tablet was placed inside the water filled dialysis bag tied at both end. This bag was suspended in a beaker containing 500 ml release media. The release media used were pH 1.2 and then pH 6.8 which were maintained at 37± 0.5⁰C and the rotation speed 50 rpm using magnetic stirrer. Whole volume of dissolution medium was replaced after each sample with fresh medium. Samples were diluted appropriately and the concentrations of DOM were determined using UV spectrometer ¹⁶.

RESULTS AND DISCUSSION:

Preparation and characterization of PEG based solid dispersions of DOM:

Solubility of DOM in distilled water was found 6.43± 0.89μg/ml. Solid dispersions were prepared by melting method using PEG. Solid dispersions of DOM were prepared at different drug and polymer ratios. The maximum solubility enhancement of 47.37±2.80 μg/ml was observed in the DOM:PEG solid dispersion at ratio 1:3 (Figure 1). This molecular dispersion was further confirmed by solid state spectroscopic analysis.

FTIR patterns of DOM, PEG, physical mixture and solid dispersion at different ratio is shown in Figure 2. DOM have characteristic peak of NH stretching at 3124.75 cm^-1 and 3021.61 cm^-1. C=O stretching at 1716.8 cm^-1 also present in both DOM and physical mixture spectra. PEG4 is having characteristic O-H stretching peaks at 3426.51 cm^-1 which also present in physical mixture. But intensity of both NH stretching peaks was reduced in SDs of PEG. This reduction was more in 1:3 SD among all. The NH bending at 1621.86 cm^-1 was also reduced significantly in same manner. This indicates hydrogen bonding formation in SD due to molecular level dispersion of DOM in molten PEG. Thus molecular dispersion of drug in PEG matrix was observed due to SD formation ¹⁷.

Figure 1 Solubility profile of PEG 4000 based solid dispersions

Figure 2 FTIR spectra of PEG based (a) DOM (b) PEG (c) SD 1:1 (d) SD 1:2 and (e) SD 1:3.

Figure 3 DSC thermo grams of (a) DOM (b) physical mixture (c) PEG based SD 1:1 and (d) SD 1:3.

Figure 3, shows the DSC curves for pure DOM, physical mixture and solid dispersions. Pure DOM exhibits a sharp melting endotherm peak at 244.22°C. Physical mixture of PEG and DOM also exhibited a sharp endotherm peak at 244.39°C for DOM and a large peak at 59.54°C which belongs to PEG. The melting points of both PEG and DOM were reduced for SD 1:1, which indicates the formation of eutectic. The intensity of DOM peak was also reduced in SD 1:1 and SD 1:3. This reduction in peak of DOM was indicating reduction in crystallinity of DOM in SD. This more reduction of DOM peak suggests that DOM is present in less crystalline form in SD 1:3. Similar enhancement in solubility due to reduction in crystallinity of drug was also reported by several authors ^7,18. This crystallinity reduction was further evaluated by XRD pattern. XRD patterns of pure DOM, PEG, physical mixture and SD are shown in Figure 4. XRD pattern of pure DOM contains characteristic intense crystalline peaks at 2 theta, 9.25, 13.9, 14.92, 15.57, 19.81, 21.47, 22.67, 24.8, 26.76 and 27.49 theta. PEG pattern also having characteristic intense crystalline peaks at 19.24 and 23.33 theta. Physical mixture pattern contains superimposed peaks of PEG and DOM.

However, in SDs all drugs peaks intensities were reduced significantly which indicate reduction in DOM crystallinity after SD formation^19,20. The maximum reduction in peaks intensity was observed for SD1:3 which is in conformity with DSC results. After solubility studies and characterization of SD, 1:3 was selected as optimum ratio for further studies.

Preparation and characterization of solid dispersion sustained release granules (SDSR):

SD of DOM was prepared for solubility enhancement of DOM. Further in order to sustain the release we treated SD with lipid, stearic acid. SD of PEG in 1:3 was selected for SDSR granules preparation. 200 mg PEG SD (50 mg DOM and 150 mg PEG) fine particles were dispersed into molten stearic acid. In order to investigate the integrity of SD in SDSR different XRD patterns were compared as shown in Figure 5. As we already discussed in earlier section, the SD of DOM had identical XRD pattern. 1:3 SD’s XRD pattern (Figure 5b) contains reduced DOM peaks at 9.32, 13.96, 14.98, 15.63, 19.86, 24.88, 26.78 and 27.58theta. Same pattern of SD was also present in physical mixture of SD and SA (Figure 5d).

Figure 4 XRD patterns of (a) DOM (b) PEG (c) physical mixture (d) PEG based SD 1:1 (e) SD 1:2 and (f) SD 1:3.

If SDs integrity was not changed during molten lipid treatment than XRD pattern of SDSR granules must be similar to the one obtained for a physical mixture of SD and SA. The XRD pattern of SDSR granules (Figure 5e) was found similar to XRD pattern of physical mixture (Figure 5d). This suggested that the integrity of SD system of DOM was remained unaffected during SDSR formation. For further confirmation of SD stability in SDSR granules formation, the XRD pattern of SDSR granules was also compared with the XRD pattern of DOM dispersion in molten stearic acid. If SD would have been destabilized during lipid treatment than the free drug might be dispersed in molten lipid and its XRD pattern should be similar to the XRD pattern of DOM dispersion in molten stearic acid. The XRD pattern of DOM dispersion in molten stearic acid was different from the XRD pattern of SDSR granules, as shown in Fig 5e and &5f. It indicates that the drug was not partitioned from the SD into molten lipid during formation of SDSR granules.

Figure 5 XRD patterns of (a) DOM (b) PEG SD (1:3) (c) SA (d) Physical mixture of PEG SD and SA (e) SDSR granules (f) DOM in lipid.

Further, the effect of lipid concentration on drug release was studied. Different lipid concentrations from 50-200 mg were used in order to sustain the release of DOM solid dispersion as shown in Table 1. Drug release study profiles of SDSR granules at different lipid concentration are shown in Figure 6. At 0% concentration of SA, more than 81% drug was released within 4 hrs. As the lipid concentration was increased, the release of drug was also sustained. At 200 mg SA less than 40% drug was released after 12 hrs. At 50 mg SA concentration, more than 96% drug release was observed after 12 hr. For further formulation development 50 mg SA treated SDSR granules were selected due to its optimum sustained drug release profile up to 12 hrs.

Table 1 SDSR granules with varying levels of stearic acids

S. No	SD (1:3) (mg)	Stearic acid (mg)
G1	200	0
G2	200	50
G3	200	100
G4	200	200

Figure 6 Cumulative percent drug release profile of SDSR granules.

Preparation and evaluation of oro-dispersible tablets of solid dispersion sustained release granules (OD- SDSR):

Different oro-dispersible tablets were prepared by direct compression (Table 2). Properties like hardness, friability, and drug content of tablets of all the batches were found to be within acceptable limits as shown in Table 3. Weight variation was also found within pharmacopoeial limit. The disintegration of tablets was performed in disintegration apparatus using 900 ml of medium without using plastic disks. However, these conditions are not comparable with in-vivo conditions where limited volume of saliva (2-8 ml/min) and lack of agitation associated under normal conditions. A modified method was also used to simulate more in vivo conditions, in which small volume of water (4 ml) was used in a test tube with minimal agitation. This modified method simulates the small oral area, the small saliva volume and the static conditions of human oral cavity. The DT values for modified method were found higher than pharmacopoeia method (Table 4 & Figure 7).

Table 2 Composition of oro-dispersible tablets of SDSR granules.

Formulation code	SDSR granules (mg)	Ac-Di-Sol (mg)	MCC (mg)	Magnesium stearate (mg)	Talc (mg)
F1	250	25	50	8	5
F2	250	50	50	8	5
F3	250	75	50	8	5
F4	250	100	50	8	5
F5	250	150	50	8	5

Table 3 Evaluation results of oro-dispersible tablet.

Formulation code	Thickness (mm)	Drug content (%)	Friability (%)	Hardness (N)
F1	4.1	99.65	0.21	41.23 ± 3.1
F2	4.3	99.67	0.33	43.1±2.1
F3	4.4	99.41	0.32	38.25±3.3
F4	4.5	98.98	0.24	40.02±2.2
F5	4.7	99.08	0.31	39.34±1.2

Table 4 Disintegration time evaluation data.

Formulation code	Disintegration time (s)	DT by modified method
F1	153±3	195±4
F2	90±4	137±3
F3	38±3	62±2
F4	21±3	39±2
F5	23±2	35±3

Figure 7 Comparison of modified and pharmacopoeial disintegration time of different formulations.

Figure 8 Disintegration of OD-SDSR tablet F4 with small volume of water (a) 0 sec. (b) 5 sec. (c) 15 sec. (d) 30 sec.

From Table 4 it is observed that formulation, F4 and F5, containing SDSR granules of DOM and 100 mg Ac-Di-Sol showed faster disintegration, within 39±2 seconds. Ac-Di-Sol works on swelling actions for rapid disintegration. In our previous trials we found that small concentration of Ac-Di-Sol was not able to disintegrate tablets of SDSR granules rapidly. This might be due to hydrophobic tendency of SA present in SDSR granules so higher amount of Ac-Di-Sol was needed to reduce the disintegration time. However, it is reported in literature that at higher concentration Ac-Di-Sol also form thick gel which reduces water penetration²¹ (Setty et al., 2008). This is why at higher concentration of Ac-Di-Sol thick gel acts as barrier for tablet disintegration. To improve water penetration into hydrophobic tablet for rapid disintegration microcrystalline cellulose (MCC) was added in the tablet formulations. MCC has good wicking and absorbing capacities. MCC allows the rapid passage of water into the tablets resulting in the instantaneous rupture of the hydrogen bonds²². Water penetration also counteract gel barrier of Ac-Di-Sol and allows rapid swelling of Ac-Di-Sol to break tablet of SDSR granules rapidly. Disintegration profile of formulation F4 is shown in Figure 8. Finally drug release profile of OD-SDSR tablet of DOM (F4) was compared with SDSR granules (G2). Almost similar release pattern was observed for both which suggests minimal effect of tablet processing on drug release profile (Figure 9). Further drug release data was fitted with different kinetic models for determination of drug release mechanism. The data for different kinetic models is given in Table 5.

Table 5 Table showing straight line equation and R2 value of different models

Model	R²	Equation
Zero order	0.337	Y = 0.0767x + 0.1497
First order	0.9499	Y = -0.1114x + 0.0829
Higuchi	0.9933	Y = 0.3226x – 0.1257
Korsmeyer-peppas	0.9897	Y = 0.6588x – 0.6955

On the basis of highest correlation coefficient value Higuchi kinetic model was found suitable for tablet. Further value of n from Korsemeyer peppas equation was found 0.6588 which indicates anomalous drug transport. This suggests both diffusion and erosion were responsible for drug release from SDSR system.

CONCLUSIONS:

Solid dispersions of DOM were successfully prepared using melting method. Molecular dispersion of DOM in PEG was achieved at 1:3 DOM and PEG ratio with highest solubility enhancement. SDSR granules were formed by treatment of DOM solid dispersion with molten SA. XRD investigation showed that SD’s integrity was remained unaffected even after molten lipid treatment. Further sustained release of DOM was also successfully achieved up to 12 hrs with SDSR granules. The drug release was found depended on lipid concentration. Finally, OD-SDSR tablets of SDSR granules were prepared by direct compression for improvement of patient compliance in those patients where swallowing might be responsible for poor patient compliance. The superdisintegrant Ac-Di-Sol was not able to disintegrate OD-SDSR tablets alonely. The presence of MCC was found necessary for rapid disintegration of OD-SDSR tablets.

ACKNOWLEDGEMENTS:

Authors are grateful to Sophisticated Analytical Instrumentation Facilities (SAIF), Panjab Univeristy for providing XRD and IIT Roorkee for providing FTIR and DSC facilities.

DECLARATION OF INTEREST:

The authors report no declaration of interest.

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Received on 16.06.2017 Modified on 21.07.2017

Research J. Pharm. and Tech 2017; 10(10):3253-3259.

DOI: 10.5958/0974-360X.2017.00577.7