Solid dispersion is molecular dispersion of drug in a polymer matrix which leads to improved solubility and hence better bioavailability. Solvent evaporation technique was employed to prepare films of different combinations of polymers, plasticizer, and a modal drug sulindac to narrow down on a few polymer-plasticizer-sulindac combinations. The sulindac-polymer-plasticizer combination that was stable with good film forming properties was processed by hot melt mixing, a technique close to hot melt extrusion, to predict its behavior in a hot melt extrusion process. Hot melt mixing is not a substitute to hot melt extrusion but is an aid in predicting the formation of molecularly dispersed form of a given set of drug-polymer-plasticizer combination in a hot melt extrusion process. The formulations were characterized by advanced techniques like optical microscopy, differential scanning calorimetry, hot stage microscopy, dynamic vapor sorption, and X-ray diffraction. Subsequently, the best drug-polymer-plasticizer combination obtained by hot melt mixing was subjected to hot melt extrusion process to validate the usefulness of hot melt mixing as a predictive tool in hot melt extrusion process.
Amorphization of drug increases the solubility of drug because of increased surface area and better ability of the solvent to wet the drug. Such a process can improve the bioavailability of drugs that are poorly soluble, namely, BCS class II and BCS class IV drugs [
Sulindac (SUL) is a nonsteroidal anti-inflammatory agent belonging to BCS class II, the absorption of which is dissolution rate limited. Solubility of SUL is 56
In the current investigation, a systematic approach is described that can be used for development of hot melt mix/extrudates of drugs with varying physical properties (Scheme
Approach for screening and selection of polymer and its combination with plasticizer.
Glyceryl behenate (GB) and hydroxyl propyl methyl cellulose (HPMC) were obtained from Colorcon India Pvt. Ltd., Mumbai, India. Lauroyl macrogolglycerides (LM) and stearoyl macrogolglycerides (SM) were obtained from Gattefosse India Pvt. Ltd., Mumbai, India. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (57 : 30 : 13) graft copolymer (PPP), copovidone (CO), povidone (PO), poloxamer 407 (P407), and glycerol polyethylene glycol oxystearate (C 40) were obtained from BASF India Ltd., Mumbai, India. Glyceryl monostearate (GM), D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), hydroxypropyl cellulose (HPC), chitosan (CHI), PEG1000, and triethyl citrate (TEC) were obtained from Sasol, Cognis Corporation, Aqualon Hercules, Sigma Life Sciences, and Merck and Aldrich Chemistry, respectively. Sulindac was obtained from Piramal Healthcare Limited, Mumbai, India. All solvents and reagents used were of analytical grade unless otherwise specified.
Experiments were carried out to determine the right combination of polymer-plasticizer concentration that could yield clear and transparent films (approximate diameter ~2 cm). The polymer and plasticizer in different ratios were dissolved in solvent/mixture of solvents (as described in Scheme
Different polymers and plasticizers along with drug tested by film technique.
Polymera | Plasticizerb | Solvent usedc |
---|---|---|
GB, LM, SM, PPP, CO, PO, P407, GM, TPGS, HPC | — | Chloroform (25–50 mg/mL) |
HPMC | — | Methanol : dichloromethane (2 : 1, 25 mg/mL) |
Chitosan | — | Water : glacial acetic acid (2 : 1, 20 mg/mL) |
— | PEG1000, PEG1000, TEC, C 40 | Soluble/miscible with ethanol and chloroform |
bPlasticizers are used in the study at two levels of 10% w/w and 20% w/w of polymer.
cValues in the parenthesis are the solubility of the polymer in the given solvent.
The films after complete drying were observed visually for smoothness and absence of any cracks or drug precipitate. For the purpose of optical microscopy (Leica Microsystems, Germany), the films were observed in crosspolarized light incident at 90° at magnification of 40x and recorded digitally (color video camera, JVC, India) using Leica QWin V3 software. In case of drug containing films, the precipitate of drug was observed as a sign of crystalline substance present at the concentration tested for drug-polymer-plasticizer.
In order to mimic the process of HME, a technique was developed wherein drug, polymer, and plasticizer (Table
Formulations of solid dispersion by hot melt mixing.
Formula | Drug (mg) | PPP (mg)a | HPC (mg)a | HPMC (mg)a | PEG1000 (mg)b | TEC (mg)b | % Yieldc | % Drug content |
---|---|---|---|---|---|---|---|---|
A | 20 | 100 | — | — | 20 | — | 89.07 | 100.46 |
B | 20 | 100 | — | — | — | 20 | 77.18 | 99.66 |
C | 20 | — | 100 | — | 20 | — | 98.90 | 108.88 |
D | 20 | — | 100 | — | — | 20 | 93.86 | 98.64 |
E | 20 | — | — | 100 | 20 | — | 98.51 | 94.06 |
F | 20 | — | — | 100 | — | 20 | 96.64 | 103.12 |
bThe plasticizers selected for hot melt mixing at a concentration of 20% w/w of polymer concentration.
cThe % yield was determined by dividing the total weight of formulation obtained after hot melt mixing process with the total weight of polymer, plasticizer, and SUL used to prepare the formulation.
d% content was determined by extracting SUL in suitable solvent and analyzing the SUL content by UV spectroscopy at 327 nm.
To confirm the presence of molecularly dispersed form of SUL in formulations described in Table
A small quantity (~1 mg) of SUL and formulations described in Table
About (~3 mg) of SUL and different formulations was assessed by X-ray powder diffraction (D-8 advanced type Bruker instrument). The samples were exposed to CuK
Solubility of SUL and its formulations was determined in water, pH 1.2, pH 4.5, pH 6.8, and pH 7.4. The buffers were prepared as described in USP (USP 30 NF 25, Volume 1). Briefly SUL (15 mg) or its formulations (15 mg equivalent) were placed in a glass vial followed by solvent (3 mL) addition and cyclomixing for 30 sec (Vortex-Genie 2, Scientific Industries, USA). The glass vials were then placed in temperature control bath (BS-21, Lab Companion, Malaysia) at 37°C for a total duration of 24 hours. Intermittently, the vials were checked for complete solubility of SUL and if required more amounts of SUL or its formulations were added. After 24 hours, the solution was filtered through 0.45
Solid state stability of the formulations was carried out in stability chambers maintained at different temperatures and durations (25°C/65% RH for 15 days, 40°C/75% RH for 15 days, 50°C for 3 days, and 100°C for 3 days). The formulations evaluated were SUL + PPP + PEG1000, SUL + PPP + TEC, SUL + HPC + PEG1000, SUL + HPC + TEC, SUL + HPMC + PEG1000, and SUL + HPMC + TEC. For the purpose of sample preparation the required amount of SUL or its formulations was placed in clear glass vials, closed with rubber closure, and sealed with aluminium cap. The samples after predetermined time were analyzed by DSC and X-ray diffraction for their thermal stability and stability towards formation of drug crystals.
Based on the solubility and solid state stability data, few formulations listed in Table
After the screening of different drug-polymer-plasticizer combinations, the optimal combination of the three that provided the best amorphization of SUL and improved solubility and better stability was selected for performing extrusion on a lab scale hot melt extruder (Thermo Scientific, Pharma II hot melt extruder). A combination of SUL (20% w/w of PPP), PPP, and PEG1000 (20% w/w of PPP) was selected based on its solubility, solid state stability, and physical characterization. The process parameters were as set at torque of 30%–40%, with a screw speed of 100 rpm; process temperature was programmed in an increasing mode starting at 115°C, increased to 130°C in second phase and the final phase maintained at 145°C in the different heating zones. The obtained hot melt extrudates were characterized by DSC and X-ray diffraction studies to confirm the presence of molecularly dispersed SUL.
The visual and optical analysis of the films using crosspolarized light at 90° are shown in Figure
Images of films obtained after evaporation of solvent after 24 hours. All the images on the Left are taken by a high resolution digital camera and the images on the right are taken with an optical microscope using a crosspolarized light at 90°. Film of glyceryl monostearate with 20% w/w TEC as observed by visual (a1) and optical microscopy (a2), film of hydroxypropyl methyl cellulose with 20% w/w TEC as observed by visual (b1) and optical microscopy (b2), film of hydroxyl propyl cellulose with 20% w/w PEG1000 and 20% w/w sulindac as observed by visual (c1) and optical microscopy (c2), film of chitosan with 20% w/w glycerol polyethylene glycol oxystearate and 50% w/w sulindac as observed by visual (d1) and optical microscopy (d2), film of povidone with 20% w/w C 40 as observed by visual (e1) and optical microscopy (e2), crystals of sulindac as observed under bight field (f1) and polarized light at 90° (f2) by optical microscope.
A bright field and polarized light microscopic image of SUL are shown in Figures
Optical microscopic image (40x magnification) using crosspolarized light at 90° for batches described in Table
The % yield of SUL hot melt mix was determined (Table
Thermal analysis by DSC for SUL showed a sharp endotherm at 188°C as observed in Figure
DSC thermograms of SUL and formulations described in Table
The hot stage microscopy images are shown in Figure
Hot stage microscopy study of formulations described in Table
As can be seen in Figure
X-ray diffraction pattern of SUL and its various formulations described in Table
The solubility of SUL and its formulations is shown in Figure
Solubility of sulindac and its formulations described in Table
Solid state stability results based on DSC (Figure
Solid state stability of different formulations described in Table
As shown in Figure
Dynamic vapor sorption plot of SUL + PPP + PEG1000, SUL + HPC + PEG1000, and SUL + HPMC + PEG1000.
Based on the initial film screening technique followed by screening using hot melt mixing a final combination of drug-polymer-plasticizer was selected for hot melt extrusion. The formula consisted of SUL (20% w/w of polymer), PPP, and PEG1000 (20% w/w of polymer). To validate the claim of hot melt mixing as a preliminary tool for selecting right drug-polymer-plasticizer combination using minimal amount of drug, DSC and X-ray (Figure
DSC and X-ray diffraction of hot melt extrudates prepared using SUL (20% w/w) and PPP and PEG1000 (20% w/w) using a mini lab extruder.
To formulate molecularly dispersed form of drug a streamlined approach for selecting the right drug-polymer-plasticizer based on film casting technique is described. Hot melt mixing mimicking hot melt extrusion is described to ascertain the possibility of forming solid dispersions using HME. Optical microscopic analysis of the polymer-plasticizer films revealed potential combinations that could be used for their combination with SUL. The polymer-plasticizer combination that gave a clear and smooth film was selected for screening with drug. C 40 did not give smooth films with most of the polymers. Films prepared from polymers (PPP, PO, CO, HPC, HPMC, and chitosan) using PEG1000 (20% w/w) and TEC (20% w/w) as plasticizers were chosen for further studies with sulindac due to their superiority in terms of visual appearance and optical microscopic analysis. The polymers studied for their feasibility in hot melt mixing process were PPP, HPC, and HPMC (these polymers formed superior films with sulindac) with PEG1000 (20% w/w) and TEC (20% w/w) as the plasticizers and the drug concentration fixed at 20% w/w. All the polymers that were tested with sulindac for their feasibility in hot melt mixing process gave uniform dispersion without presence of drug, polymer, or plasticizer pockets in the matrix. The dispersion of sulindac with PPP was visible as a solid solution whilst that with HPMC and HPC was a uniform dispersion. Dispersions containing TEC as a plasticizer had more binding strength and rigidity as compared to dispersions consisting of PEG1000 as a plasticizer. The technique developed for hot melt mixing gave the drug content of close to 100% indicating homogeneity and accuracy of the process. DSC analysis of the dispersions prepared by hot melt mixing process confirmed the presence of sulindac in molecularly dispersed form as no endothermic event was evident. Dispersions of HPC and HPMC containing PEG1000 as the plasticizer gave a broad endotherm at 56°C for PEG1000 suggesting possible separation of PEG1000 from the dispersion due to faster cooling rate of PEG1000 as compared to other constituents. Hot stage microscopy studies validated the results obtained by DSC. No endothermic event was observed at 188°C. All the thermal events that were observed were at temperatures other than the melting point of SUL. X-ray diffraction study of all the formulations confirmed the molecular dispersion of SUL in different polymers. The characteristic peaks of SUL were either absent or subdued in all the polymer-plasticizer tested. Solubility of sulindac was checked in water and buffers (pH 1.2 to 7.4) to ascertain the increase in solubility of sulindac in dispersion as compared to only sulindac. Promising results were obtained for all the dispersions tested as there was significant increase in solubility in water as well as in all buffers tested. There was an 8.5-fold increase in solubility for dispersion containing sulindac, HPMC, and TEC in water. Almost 40-fold increase in sulindac solubility at pH 1.2 was observed for dispersion containing sulindac, PPP, and TEC. An 11-fold increase in solubility at pH 4.5 was observed for dispersions containing sulindac, HPMC, and TEC or PEG1000. As the pKa of sulindac is 4.7, there is bound to be an increase in its solubility above this pH due to formation of salts. This was evident as there was a drastic change in solubility of sulindac in free form and or its conjugation in form of dispersion. At pH 6.8 there was an 8-fold increase in solubility for dispersion containing sulindac, PPP, and PEG1000 or TEC. At pH 7.4 there was a twofold increase in solubility for dispersion of sulindac with HPC and PEG1000 as well as HPMC and TEC. All the polymers tested showed a significant increase in solubility of sulindac with dispersions containing TEC as the plasticizer showing higher solubilization power. On further investigation it was confirmed that sulindac is soluble in TEC (liquid at room temperature) and thus can accommodate drug in its matrix leading to enhanced solubilization of sulindac. The solid state stability showed that the TEC as a plasticizer, although showing better solubilization potential of SUL, did not hold the drug in molecularly dispersed form upon subjecting it to stressed solid state stability studies. This was evident in DSC thermograms of combinations containing TEC as plasticizer. HPC did not produce stable dispersions as upon storage there was a tendency of SUL to convert to a more stable crystalline form evident from DSC thermograms. Based on solid state stability data, formulations containing SUL + PPP + PEG1000 and SUL + HPMC + PEG1000 were stable under tested conditions. Also the dynamic vapor sorption analysis suggested better stability of these two formulations with both the formulations absorbing not more than 5% by weight when exposed to 80% relative humidity. The claim that hot melt mixing can be used as a screening technique prior to hot melt extrusion was validated as the combination of SUL + PPP + PEG1000 as obtained by hot melt mixing was able to produce solid dispersions when subjected to hot melt extrusion using a mini lab extruder as confirmed by DSC and X-ray diffraction results.
A fast and effective screening technique to develop stable solid dispersions for a poorly soluble drug is successfully developed. The given method of hot melt mixing is easy to use, requires less quantity of drug (advantageous for developing solid dispersions of new chemical entities), and is fairly accurate in predicting the amorphization of the drug in formulation.
The authors report no conflict of interests regarding the publication of this paper.