INTRODUCTION:

A number of approaches were employed to overcome the problems of the formulation development of poorly soluble drug molecules^1.Among these, the most widely followed approach is to utilize an amorphous form of drug compound to achieve good oral bioavailability². The amorphous compounds have higher dissolution when compared to their crystalline counterparts. Drugs which belong to class II of the biopharmaceutical classification system (BCS) are characterized by high membrane permeability but slow dissolution rate (due to low aqueous solubility) and have bioavailability problems³. Although there are several methods available for dissolution enhancement, all of them may not be suitable for all drugs.

Because the approach employed will depend on based on the drug’s physicochemical properties. While developing a fast dissolving product, care has to be taken to ensure the physical stability of the amorphous form⁴.

In the present investigation, a poorly soluble drug, indomethacin was employed as model drug to comparatively evaluate the efficacy of the solid dispersion and inclusion complexation methods to enhance its dissolution. Indomethacin a class II category drug as per biopharmaceutical classification system (BCS), is anti-inflammatory agent that is used in the treatment of rheumatoid arthritis and osteoarthritis⁵. Combination of polymers were employed to prepare the solid dispersions or the inclusion complexes to find out their suitability for preparing the fast dissolving and stable products. Binary solid dispersions in gelucire (50/13) were initially prepared and the influence of soluplus (a ternary dispersion) was investigated. Similarly inclusion complexes in sulfobutyl ether were prepared and further evaluated by preparing a ternary inclusion complex in the presence of gelucire.

Gelucires are a novel class of synthetic polymers derived from mixtures of mono-, di-, and triglycerides with polyethylene glycol (PEG) esters of fatty acids. The gelucires containing only PEG esters (Gelucire 44/14 or 50/13) are hydrophilic and generally are used in preparation of fast-release formulations⁶. Soluplus, a polyethylene glycol-polyvinyl caprolactam acetate grafted copolymer, is a novel thermoplastic internally plasticized amphiphilic polymer particularly made for use in formulating solid dispersions. Soluplus, a fourth generation solid dispersion polymer is miscible with water in any ratio and also shows good solubility in many organic solvents^7,8. Soluplus was used as polymer to prepare amorphous solid dispersions of poorly soluble drugs^9,10. Although gelucires and soluplus are studied individually for preparing solid dispersions, investigations are not carried out on the possible synergistic effect that the two polymers in a dispersion can have on the dissolution of drugs.

Inclusion complexation is another approach that is used to prepare fast dissolving amorphous forms of drugs. Different approaches are employed to prepare inclusion complexes^11,12.Sulfobutyl ether-beta-cyclodextrin (SBE₇ -β-CD) is a modified β cyclodextrin that has higher drug entrapment ability, better physical, and chemical properties than the parent cyclodextrin^13,14. SBE₇ -β-CD, is reported to be safe after intensive chronic safety evaluation^15.The binary and ternary dispersions and inclusion complexes are comparatively characterized which is essential to assess the physicochemical properties of high dissolving forms to design oral formulations with optimum drug dissolution.

MATERIALS AND METHODS:

Materials:

Indomethacin (gift sample from Julphar Gulf Pharmaceutical Industries), sulfobutyl ether beta cyclodextrin (Captisol - Cydex Corp, USA), Gelucire (50/13) is a gift sample from Gattefosee, France. Soluplus is a gift sample from BASF, Germany. Other polymers such as microcrystalline cellulose are locally procured. All solvents and reagents are of analytical grade.

Preparation of fast dissolving products of indomethacin:

Indomethacin binary solid dispersion:

Solvent evaporation method:

50mg of indomethacin was accurately weighed and transferred to a round bottom flask of 50ml volume and dissolved in 25ml of methanol. Then 100mg of Gelucire was added to the solution and dissolved completely, then 350mg microcrystalline cellulose was added to the solution which is then agitated with a magnetic stirrer. The solvent was then evaporated leaving behind a solid residue. The residual mass obtained after solvent removal was then kept in the desiccator overnight and then ground to fine powder and passed through 100-mesh sieve.

Freeze drying method:

50mg of indomethacin was weighed and transferred to a conical flask and dissolved in 10ml of methanol. In a separate flask 100mg of gelucire was dissolved in 25ml of water. Then the 2 solutions were combined and 350 mg of microcrystalline cellulose was added and the mixture was then agitated with a magnetic stirrer. The obtained mixture was then transferred into the freeze drying jar and kept in the freezer for 24 hours at -70^oC. Then the sample was kept in the freeze dryer (SP Scientific Model No Model PRO 3XL) for 24 hours and the dried at -70^oC and 26 Torr. The solid mass was ground to fine powder and passed through 100-mesh sieve.

Preparation of indomethacin ternary solid dispersion:

The ternary solid dispersion of indomethacin was prepared using solvent evaporation and freeze drying methods as described before where for the ternary solid dispersion, soluplus (5% w/w) was incorporated during the preparation.

Preparation of indomethacin inclusion complex:

Preparation of indomethacin binary inclusion complex:

Phase solubility studies were done to determine the molar ratio of complex formation as per Higuchi and Connors method¹⁶. The phase solubility study was done by adding excess amounts of indomethacin to an increasing concentrations of sulfobutyl ether beta cyclodextrin (2-10mM) prepared in 15ml distilled water. Now the suspensions were kept in a mechanical shaker and shaken at 25±0.5°C for 72 hours. After equilibration, the aliquots were withdrawn, necessary dilutions were made and assayed for indomethacin at 318nm. From the results of the phase solubility (discussed under results section), it is found that the inclusion complex is formed in 1:1 molar ratio and accordingly, the complexes are prepared in 1:1 molar ratio. The indomethacin inclusion complexes were prepared by kneading method and freeze drying methods.

Kneading method:

The required amount indomethacin and sulfobutyl ether beta cyclodextrin were weighed accurately and transferred into a mortar and a small volume of distilled water was added and kneaded for 20 min. After drying the obtained solid mass was then ground to fine powder and passed through 100-mesh sieve.

Freeze drying method:

Indomethacin was weighed and transferred to a conical flask and dissolved in 10ml of methanol. In a separate flask the calculated amount of sulfobutyl ether beta cyclodextrin was dissolved in 25ml of water. Then the two solutions were combined and the mixture was then agitated with a magnetic stirrer. The obtained mixture was then transferred into the freeze drying jar and kept in the freezer for 24 hours at -70^oC and 26 Torr. Then the sample was subjected to drying in the freeze dryer for 24hours after that the obtained solid was ground to fine powder and passed through 100-mesh sieve.

Preparation of indomethacin ternary inclusion complex:

The ternary inclusion complexes were prepared as before where for the ternary inclusion complex, gelucire (0.8%) was incorporated during the preparation.

Characterization of prepared solid dispersions and inclusion complexes:

Flow properties:

The prepared solid dispersions and inclusion complexes were evaluated for angle of repose, Carr’s index and Hausner ratio to determine their flow properties. The results of the flow properties of different products are given in Table 1.

Drug content:

From each batch, three samples of 10mg each of the solid dispersions and inclusion complexes were taken and analyzed for indomethacin content. The weighed solid dispersions or inclusion complexes were taken into 10ml volumetric flasks and dissolved in 10ml of methanol and then diluted as needed and assayed for indomethacin content by measuring absorbance at 318 nm.

Dissolution studies:

The drug dissolution study of the various solid dispersions and inclusion complexes were performed by employing USP Dissolution Rate Test Apparatus Type II employing a paddle stirrer employing 0.1N Hydrochloric acid as dissolution medium for 1hour. The samples of the medium were withdrawn at regular intervals and replaced by fresh medium and the absorbance of the filtered samples were measured at 318 nm.

X-ray diffraction studies:

The pure drug indomethacin, the various solid dispersions and the inclusion complexes prepared were subjected to X-ray diffraction analysis to determine the physical characteristic of the drug. The X-ray powder diffractometer (PANAnalytical Model No: Xpert Pro) was operated employing Cu Ka radiation. The diffractograms were run between 2° and 40° at 2°/min in terms of 2^qangle.

Differential scanning calorimetry studies:

The pure drug indomethacin, the various solid dispersions and the inclusion complexes prepared were subjected to differential scanning calorimetric analysis employing a calorimeter (Model-Shimadzu-DSC 60+) which was operated at a scanning rate of 10°C per minute and heated from 25°C to 350°C. The samples were sealed in aluminum pans and heated in a constant inert atmosphere maintained by purging nitrogen gas at a flow rate of 10ml/min.

FTIR studies:

The pure drugs, indomethacin, and the various solid dispersions and inclusion complex prepared were subjected to FTIR analysis using Fourier transform infrared spectrophotometer (Agilent Model Cary 630). Attenuated total reflectance (ATR) sampling interface was used to obtain the spectra.

Scanning electron microscopy (SEM):

The morphological appearance of the dispersions and inclusion complexes was investigated by employing scanning electron microscope (JEOL Instruments - JSM 7800 F). The pure drug powder, the dispersions and the complexes were mounted onto the SEM sample stub and are observed under reduced pressure employing an acceleration voltage of 15 KV

RESULTS AND DISCUSSION:

Phase solubility study:

The phase solubility curves of indomethacin in aqueous solutions of sulfobutyl ether beta cyclodextrin (SBE₇-β-CD) in the presence or absence of gelucire (0.8% w/v) are shown in figure 1. The phase solubility curves in both the cases exhibited A_L type curve as the solubility of indomethacin increased linearly with the SBE₇-β-CD concentration. The slopes of the curves are <1 suggesting that water-soluble complexes are formed in 1:1 molar ratio between indomethacin and SBE₇-β-CD ¹⁶. The stability constant values are found to be higher in the case of ternary system (K_s=756) compared to the binary system (Ks= 667). Formation of such ternary complex is normally observed with an increase in the K_S value ^17. The solubility of indomethacin is significantly promoted in the presence of gelucire. The slopes of the phase solubility curves are higher in case of ternary systems than in the case of binary system. Water-soluble polymers along with beta-cyclodextrins are reported to exhibit a synergistic solubilization effect on the solubility of poorly soluble drugs¹⁸. That is, the apparent solubility of drug is greater than the solubility obtained when the hydrophilic polymers were assessed individually. Loftsson et al. reported a similar improved complexation with relatively low polymer concentrations of between 0.1% and 1% (w/v)¹⁹.

Figure 1: Phase Solubility Diagram of Indomethacin with Sulfo Butyl Ether Beta Cyclodextrin

Flow properties:

The drug content values and flow properties of various solid dispersions and inclusion complexes are summarized in table 1. Poorly flowing powders present many difficulties during processing. The flow characteristics were evaluated by determining Hausner’s ratio, Carr's index and angle of repose. Poor flow could be because of interparticle friction and such powder particles exhibit a Hausner ratio of more than 1.25.Generally, powders with Carr's index (CI) below 25% have fair to good flow properties²⁰. Powders with angle of repose above 50° have unsatisfactory and difficult flow properties, while those of 25°-40° represent reasonable flow. In our study, the dispersions and inclusion complexes exhibited good flow properties suggesting that they are amenable for direct compression. We observed that the solid dispersions had better flow than the inclusion complexes. This better flow of solid dispersions could be due to the deposition of the dispersions on microcrystalline cellulose particles during the preparation of the fast dissolving product which resulted in discrete and free flowing powder.

Table 1 Drug content and flow properties of various solid dispersion and inclusion complexes

Product*	Drug Content (%)	Hausner ratio	Carr index	Angle of Repose
F1	9.85±.01	1.05±0.09	16.17±1.47	23.21±1.29
F2	9.38±0.59	1.13±0.11	16.35±1.72	24.41±2.15
F3	9.77±0.66	1.19±0.04	18.44±1.29	24.37±1.94
F4	9.48±1.12	1.17±0.06	15.66±2.05	22.29±2.17
F5	13.82±0.76	1.28±0.10	21.89±2.31	29.54±1.69
F6	13.45±1.21	1.26±0.07	22.51±1.19	31.58±1.87
F7	13.79±1.16	1.27±0.05	21.16±2.21	29.95±1.81
F8	13.17±0.86	1.29 ± 0.08	23.32 ± 1.45	31.41±2.05

*F1- Solid dispersion (binary/solvent evaporation); F2- Solid dispersion (ternary /solvent evaporation); F3- Solid dispersion (binary/freeze drying); F4- Solid dispersion (ternary/freeze drying); F5- Inclusion complex (binary/kneading); F6-- Inclusion complex (ternary/kneading); F7-- Inclusion complex (binary/ freeze drying);F8- Inclusion complex (ternary / freeze drying)

Dissolution studies:

The prepared inclusion complexes and solid dispersions exhibited significant increase in dissolution compared with the pure drug. The dissolution profiles are shown in Figures 2 and 3 and the various dissolution parameters are given in table 2. Solid dispersions of the drug in gelucire are found to be exhibiting higher dissolution than the inclusion complexes of indomethacin in sulfobutyl ether beta cyclodextrin. Also it is observed that ternary dispersions and inclusion complexes are more efficient in enhancing the dissolution than the binary systems. The addition of soluplus to the gelucire dispersions produced a noticeable synergistic effect in increasing the dissolution compared with the binary dispersion. As the soluble carrier of the dispersion dissolves, the drug dispersed in the carrier gets exposed to dissolution medium in the form of very fine particles. The presence of ternary component such as soluplus in the solid dispersion system, resulted in the particle size reduction of drug and the consequent increase in the surface area lead to an improved dissolution ²¹. Also the drug solubility and wettability might have been increased by surrounding hydrophilic polymer and soluplus.

Figure 2: Dissolution profiles of pure drug indomethacin and the solid dispersions

Figure 3: Dissolution profiles of pure drug indomethacin and the inclusion complexes

Table 2 Dissolution parameters of different solid dispersions and inclusion complexes

Product	Dissolution parameter
Product	Dissolution efficiency (%) DE₃₀(%)	Dissolution rate constant (K₁ ) (min⁻¹)	T₅₀ (min)	Difference factor (f₁ value)
Pure drug indomethacin	3.32	0.0051	>60	--
F1	20.11	0.0115	51	69.84
F2	53.35	0.0460	12	90.12
F3	36.68	0.0230	23	87.05
F4	73.34	0.0921	06	91.53
F5	13.34	0.0109	>60	69.23
F6	20.17	0.0114	55	77.21
F7	31.66	0.0207	29	83.53
F8	54.12	0.0461	17	90.44

Compared to the solvent evaporation method, freeze drying method is found to be yielding products which showed higher dissolution. This higher dissolution of freeze dried products could be due to the formation of the amorphous and highly porous product owing to the removal of water by sublimation. A similar observation was made by Shailesh et al., where in they reported that the freeze-drying technique resulted in greater saturation solubility of the poorly water soluble drug, roxithromycin, compared to the spray-drying and the homogenization technique²². The apparent density of the freeze-dried products is much lower than that of powders prepared by solvent evaporation which confirms the larger porosity retained in the freeze dried powders.

In the case of inclusion complexes also it is observed that the freeze drying method is found to be more efficient in improving the dissolution of indomethacin compared to the kneading method. In the kneading method, sulfo butyl ether beta cyclodextrin was probably forming inclusion complex of indomethacin by taking up some parts of the molecule into the cavity, whereas the whole drug molecule was encapsulated into the cavity when the solid inclusion complex was prepared by the freeze drying method. It has been reported that the significant improvement of in dissolution characteristics in case of the inclusion complex prepared by the freeze-dried method with HPβCD may be due to the formation of the solid inclusion complex with better interaction of the drug and HPβCD the during the freeze-drying method ²³. The ternary inclusion complex gave higher dissolution and this may be due to the addition of gelucire as a ternary substance. The presence of gelucire may help achieve better inclusion and amorphization which led to enhanced drug dissolution. A ternary substance in the drug –cyclodextrin complex induces a better interaction with the hydrophobic portion of cyclodextrin²⁴.

The dissolution data obtained was used to comparatively evaluate the influence of the method and the nature of dispersions/complexes on the ability to enhance the dissolution of indomethacin. The dissolution efficiency (DE₃₀) is calculated as per the model suggested by Khan ²⁵. Higher DE values were observed for the solid dispersion products prepared by freeze drying than the solvent evaporation. The extent of increase in dissolution observed from the various products was assessed by finding out the difference factor (f1). In between the methods, products prepared by solid dispersion are found to be showing higher f1 values than the corresponding products made by inclusion complexes. Similarly the ternary systems showed higher values compared to the binary systems. The various f1 values between the products compared are shown in Table 2.

Regression analysis of dissolution data:

The various fast dissolving products were prepared using a 2² full factorial experimental design in order to investigate the combined influence of two factors – the approach employed in the preparation of fast dissolving product (solid dispersion or inclusion complex ) and the nature of the product (binary or ternary dispersion/complex). In this design, the 2 factors are evaluated each at 2 levels and experimental trials are performed on all 4 possible combinations. The independent variables were the approach employed to prepare the product either solid dispersion or inclusion complex (X1) and the nature of dispersion/complex either binary or ternary (X2) (Table 3). The percent dissolved at 30 minutes (Y1) was selected as the dependent variable.

Table 3 design parameters and experimental conditions for 2² factorial study

Independent variable	Levels
Independent variable	-1	1
Approach employed (solid dispersion or inclusion complex	Solvent evaporation or Kneading	Freeze drying
Nature of dispersion/complex	Binary	Ternary

Data obtained on the 2 dependent variables for all formulations (F1–F8) showed a wide variation which indicated that the response values of dependent variable highly rely on the independent variables.

Data analysis of percent dissolved at 30 minutes:

The regression equation that predicts the percent released is given below:

Y1 (percent released) = 67 + 12 X₁ + 22.5 X₂(for solid dispersions)

Y1 (percent released) = 44.5 + 21 X₁ + 8 X₂(for inclusion complex)

The observed value for percent dissolved at 30 minutes for the 4 products made by solid dispersion method ranged from 31.25% to 98.65%. Correlation coefficient value was found to be 0.9965 and can be considered as a good measure of the quality of the prediction of the dependent variable using the model employed. The higher coefficient value of X2 (nature of dispersion) suggests that the nature of dispersion – binary or ternary – is having more influence on the dissolution than the method (solvent evaporation or freeze drying). On the other hand, in case of inclusion complexes, the higher value for X1 (the method of preparation) suggests that the method is having more profound effect on the dissolution rather than the nature of complex. That is freeze drying method is more effective than the kneading method. However as observed in the solid dispersions, the ternary complex is showing higher dissolution than the binary complex.

Mechanism of increased dissolution:

To assess the reason for the increased dissolution of indomethacin from the prepared dispersions and inclusion complexes, X-ray diffraction and differential scanning calorimetric studies were carried out.

X-ray diffraction:

X-ray diffraction is commonly employed for characterizing the physical state of drug. The diffraction behavior will throw light on the crystalline or amorphous nature of the drug. The X-ray diffraction spectra of indomethacin, its dispersions and inclusion complexes are shown in figures 4 and 5. The diffraction patterns of the pure indomethacin displayed crystallinity, whereas an amorphous pattern lacking crystalline peaks was observed for the various products prepared. The principal peaks attributable to indomethacin crystals were not detectable in the X-ray profiles of the solid dispersions or inclusion complexes. The disappearance of indomethacin crystalline peaks in both solid dispersions and inclusion complexes confirmed a strong drug amorphization effect. However in case of the inclusion complexes made by kneading, two peaks are still noticed which probably suggests partial amorphization in the kneading method and pure drug still has retained the crystalline domains even in the inclusion complex and this could be the reason why the kneaded systems exhibited lesser dissolution than the freeze dried inclusion complexes.

Figure 4: X-ray diffractograms of indomethacin (A); Binary solid dispersion – freeze dried (B); Binary solid dispersion – solvent evaporation (C); Ternary solid dispersion – freeze dried (D); Ternary solid dispersion – freeze dried (E)

Figure 5: X-ray diffractograms of indomethacin (A); Binary inclusion complex– freeze dried (B); Binary inclusion complex – kneading (C); Ternary inclusion complex – freeze dried (E); Ternary inclusion complex – kneading (E)

Differential scanning calorimetry (DSC):

The endotherms of indomethacin and the various products are shown in figures 6 and 7. Pure drug indomethacin showed a sharp endothermic peak at 161°C which is due to its melting point. Gelucire (50/13) showed its endothermic peak around 49°C while soluplus and SBE₇ -β-CD did not show any specific endothermic transformation. No thermodynamic transformation (melting endotherm) of indomethacin was observed in the various products prepared. The sharp endothermic peak observed in case of pure indomethacin disappeared completely. This could be due to the presence of the drug in soluble amorphous state in the solid dispersions and inclusion complexes and loss of crystallinity. This conversion of drug into amorphous form is the reason for the higher dissolution of indomethacin from the solid dispersions and complexes compared to that of the pure drug. Hence, the X-ray diffraction and DSC studies confirm the existence of indomethacin in amorphous state in the fast dissolving products prepared.

Figure 6 Differential scanning calorimetry of indomethacin (A); Binary solid dispersion – freeze dried (A1); Binary solid dispersion – solvent evaporation (A2); Ternary solid dispersion – freeze dried (A3); Ternary solid dispersion – freeze dried (A4)

Figure 7: Differential scanning calorimetry of indomethacin (A); Binary inclusion complex– freeze dried (B2); Binary inclusion complex – kneading (B1); Ternary inclusion complex – freeze dried (B4) ; Ternary inclusion complex – kneading (B3)

FTIR study:

The FTIR spectra of the pure indomethacin and some fast dissolving products are shown in figure 8. Indomethacin exhibited characteristic absorption peaks at 2925.95 cm⁻¹ (O–H stretching vibration), 1712.97 cm⁻¹ (C=O stretching of carboxylic acid dimer), 1688.77 cm⁻¹ (C=O stretching), 1601.39 cm⁻¹ (C–C aromatic ring stretching) and 1230 cm^-1((C-O) stretch plus O-H deformation) ^{26, 27}. In the various indomethacin products prepared, all the characteristic peaks of indomethacin are retained even though the intensity of peaks was reduced or broadened. The spectra showed no peaks other than those assigned to indomethacin, suggesting that there were no chemical interactions between indomethacin and the polymers used.

Figure 8: FTIR spectra of pure drug Indomethacin (A); Binary solid dispersion (B); Ternary solid dispersion (C) and binary inclusion complex (D)

Scanning electron microscopy:

The surface morphology of pure drug indomethacin, the solid dispersion and inclusion complexes prepared by freeze drying method were examined by SEM analysis and shown in in figure 9. The pure drug is irregular in shape and demonstrated a needle-like appearance, whereas no visible needle-like structures are observed in both solid dispersion and inclusion complex products and they consisted of more spherical particles with no irregular surface. The results of indicated a large difference in size and shape existed between the crystalline indomethacin and the fast dissolving products. The surface morphology studies revealed that the solid dispersion and inclusion complexation resulted in more rounded particles with smooth surfaces.

Figure 9 SEM images of pure drug indomethacin (A); Binary solid dispersion – freeze dried (B); Ternary solid dispersion – freeze dried (C); Binary inclusion complex – freeze dried (D); Ternary inclusion complex - freeze dried (E)

CONCLUSIONS:

In this investigation, we evaluated different fast dissolving products of indomethacin in terms of improving its dissolution. While all products prepared proved capable of improving the dissolution, significant differences in the extent of increase in dissolution were observed in the products prepared by different methods and based on the nature of the product. Both the solid dispersion and inclusion complexation techniques exhibited increased dissolution. However the solid dispersion in gelucire is found to be more effective than the inclusion complexation in sulfo butyl ether beta cyclodextrin. Compared to the binary systems, the ternary systems gave higher dissolution. Soluplus or gelucire are found to be useful ternary components to enhance the dissolution from solid dispersion or inclusion complexes respectively. The method of preparation of the products also influenced the extent of dissolution obtained. For example, the freeze drying method of solid dispersion is found to be more effective than the solvent evaporation and similarly the freeze drying method of inclusion complexation was found to be better than the kneading method. The crystalline drug indomethacin is converted into amorphous form in the products prepared. The increase in dissolution of indomethacin is due to the combined effect of conversion of the drug into an amorphous form and the presence of ternary component in the solid dispersion or inclusion complex. Thus the method of preparation and nature of the product influence the extent of improvement of dissolution of poorly soluble drugs. Further evaluations on stability of the ternary systems prepared in this study are necessary to confirm their usefulness and advantage over the binary dispersions and complexes.

ACKNOWLEDGMENT:

The authors express their gratitude to the President of RAK Medical and Health Sciences University, UAE and Dean RAK College of Pharmacy for their encouragement and support in carrying out the research.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 02.03.2022 Modified on 09.04.2022

Research J. Pharm. and Tech 2022; 15(12):5529-5536.

DOI: 10.52711/0974-360X.2022.00933