DSpace at VNU: Development of a modified - solid dispersion in an uncommon approach of melting method facilitating properties of a swellable polymer to enhance drug dissolution

International Journal of Pharmaceutics 484 (2015) 228–234 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical nanotechnology Development of a modified – solid dispersion in an uncommon approach of melting method facilitating properties of a swellable polymer to enhance drug dissolution Tuong Ngoc-Gia Nguyen a , Phuong Ha-Lien Tran a, * , Thanh Van Tran b , Toi Van Vo a , Thao Truong-DinhTran a, * a Pharmaceutical Engineering Laboratory, Biomedical Engineering Department, International University, Vietnam National University, Ho Chi Minh City, Vietnam b School of Pharmacy, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam A R T I C L E I N F O A B S T R A C T Article history: Received November 2014 Received in revised form 20 February 2015 Accepted 27 February 2015 Available online 28 February 2015 The study aimed to develop a modified-solid dispersion method using a swellable hydrophilic polymers accompanied by a conventional carrier to enhance the dissolution of a drug that possesses poor water solubility Two swellable polymers (hydroxypropyl methylcellulose and polyethylene oxide) were swelled in melted polyethylene glycol 6000 (PEG 6000) in different ratios and under different conditions The type, amount, and, especially, incorporation method of the swellable polymers were crucial factors affecting the dissolution rate, crystallinity, and molecular interaction of the drug Interestingly, the method in which the swellable polymer was thoroughly mixed with the melted PEG 6000 as the first step was more effective in increasing drug dissolution than the method in which the drug was introduced to the melted PEG 6000 followed by the addition of the swellable polymer This system has potential for controlling drug release due to high swelling capabilities of these polymers Therefore, the current study can be considered to be a promising model for formulations of controlled release systems containing solid dispersions ã 2015 Elsevier B.V All rights reserved Keywords: Solid dispersion Melting method Swellable polymer Poorly water-soluble drug Controlled release Introduction Solid dispersion (SD) is a potential approach in enhancing dissolution and bioavailability of poorly water-soluble drugs Advantages of the technique such as simplicity, economization, and others have been widely reported (Vasconcelos et al., 2007) There are two basic different preparation methods of SD including melting method and solvent evaporation method (Tran et al., 2009, 2010) Melting method was first demonstrated by Sekiguchi and Obi (1961) The product was prepared by melting drug with carrier, then cooling and pulverization In the melting process, high mobility of carrier would change the combination of drug (van Drooge et al., 2006) In solvent evaporation method, drug and carrier were completely dissolved in a volatile solvent such as ethanol, chloroform, or a mixture of ethanol and dichloromethane (Hasegawa et al., 2005; Lloyd et al., 1999; Rodier et al., 2005) at a low temperature to avoid thermal degradation of drug and carrier * Corresponding authors Tel.: +84 37244270x3328; fax: +84 37244271 E-mail addresses: thlphuong@hcmiu.edu.vn (P.H.-L Tran), ttdthao@hcmiu.edu.vn (T Truong-DinhTran) http://dx.doi.org/10.1016/j.ijpharm.2015.02.064 0378-5173/ ã 2015 Elsevier B.V All rights reserved (Won et al., 2005) The later method has some disadvantages such as high preparation cost, incomplete solvent removal, alteration in product performance with the change of condition applied (Vasconcelos et al., 2007) The swellable hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO) were introduced in this study to modulate drug release from a SD (Tran et al., 2011; Tran and Tran, 2013) As they are hydrophilic, these polymers may improve the solubility of poorly water-soluble drugs, and their swellable properties may be exploited to promote controlled drug release The utilization of these two polymer properties in one system might facilitate the development of specialized drug delivery systems by both enhancing drug solubility and controlling the release of poorly water-soluble drugs This hypothesis was tested herein through the preparation of SDs However, these polymers are difficult to melt at high temperatures for SD preparation On the other hand, disadvantages are usually met in the solvent method as mentioned above Moreover, drugs may be precipitated during solvent removal, leading to the failure of the method intended to enhance drug solubility Slow drug dissolution rates result when the drugs are not well distributed in the polymer Therefore, the SD method is not always a successful approach to T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 improve drug solubility Thus, in this paper, an SD system using the melting method was developed as a new feasible technique using swellable hydrophilic polymers The system was fabricated not only to increase the dissolution rates of poorly water-soluble drugs, but also to potentially control the release of those drugs Curcumin (CUR), a poorly water-soluble drug with many potential applications, was used as the model drug in this study The crystalline behaviors and molecular interactions in the system were investigated to elucidate the potential of this system Materials and methods 2.1 Materials Curcumin and sodium hydroxide (NaOH) were purchased from Guanghua Sci-Tech Company (China) Hydroxypropyl methyl cellulose (HPMC 4000, HPMC 6) and polyethylene oxide N-60K (PEO) was provided by from Dow Chemical Company (USA) Polyethylene glycol (PEG 6000) was purchased from Sino-Japan Chemical (Taiwan) Methanol (MeOH) was purchased from Fisher Scientific International, Inc (US) Hydrochloric acid (HCl) and sodium chloride (NaCl) were purchased from Xilong Chemical Industry Incorporated Company (China) Monopotassium phosphate (KH2PO4) was purchased from Wako Pure Chemical Industries (Japan) 2.2 Methods 2.2.1 Preparation of SDs Melting method was used for preparation of SDs Following are some factors that were varied to prepare different SDs for evaluation of drug release rate: swellable polymers (HPMC 6, HPMC 4000, and PEO), the polymer ratio, and combination method between drug and polymers (Table 1) The SDs were finally stored in a dry place and protected from light until further use Two combination methods were differentiated by the order of incorporation of drug and swellable polymer into melted PEG 6000 In method I, PEG 6000 and drug had been thoroughly mixed before the polymer was added in the mixture PEG 6000 was melted at 190  C, and CUR was then added under stirring until a uniform mixture was obtained Then the swellable polymer was dispersed in the mixture to obtain SDs in semisolid form which were finally cooled at room temperature (25  C) before use In method II, PEG 6000 and swellable polymer were mixed before the drug was added into the melted mixture Every other step was conducted as it was in method I The melting temperature was controlled and the mixture was stirred on digital stirring hot plates (Thermo Scientific, Germany) during the preparation process 2.2.2 Dissolution studies Drug dissolution was studied with SDs at 37 Ỉ 0.5  C (50 rpm, paddle apparatus, DT70 Pharmatest, Germany) according to the 229 USP 30 pharmacopoeia Buffer (pH 1.2 or pH 6.8, 900 ml in each dissolution vessel) was used as the dissolution medium Sample aliquots (1 ml) were collected from the media at predetermined intervals of 10, 20, 30, 60, 90, and 120 ml of withdrawn sample was compensated by adding ml of the corresponding fresh buffer 2.2.3 HPLC analysis The quantification of CUR was performed using an Ultimate 3000 HPLC system (Thermoscientific Inc., USA) The mobile phase was 4:1 methanol/acetic acid 2% The flow rate was maintained at 1.2 ml/min The UV/vis detector was set to a wavelength of 425 nm 20 ml of sample was injected to HPLC system 2.2.4 Characterization by X-ray diffraction (PXRD) In this study, pure CUR, PEG 6000, HPMC 4000, physical mixture (PM), and SDs were analyzed by PXRD Diffraction patterns were recorded by a Powder X-ray diffractometer (Bruker’ D8 Advance Series PXRD, Germany) using Ni-filtered, CuKa (l = 1.54060 Å) radiation at a voltage of 40 kV and at a current of 40 mA Samples were held on quartz frame The sample was scanned in a 2u from 5 to 50 with a receiving slit 0.1 mm (a step size of 0.021 at 2u /s) 2.2.5 Characterization by Fourier transform infrared spectroscopy (FTIR) The physicochemical properties of CUR, PEG 6000, HPMC 4000, PM, and SDs were characterized by using a Bruker Vertex 79 FTIR spectrometer (Germany) KBr pellets were prepared by mixing mg of samples with 200 mg KBr The wavelength was 500– 4000 cmÀ1 and the resolution was cmÀ1 2.2.6 Solubility test Excess CUR was added to the tubes containing ml of various media (pH 1.2 and pH 6.8) The resulting mixtures were shaken at 100 rpm at 37  C for 48 h in a water bath The tubes were then centrifuged at 13,000 rpm for 15 The supernatant was diluted for the determination of drug concentration by HPLC 2.2.7 Statistical analysis All data were presented as mean Ỉ standard deviation The statistical significance of the differences was determined using an analysis of variance (ANOVA) (P < 0.05 or 0.01) Results and discussion 3.1 Dissolution and solubility studies Our preliminary study showed that CUR was poorly soluble and had lower solubility in acidic medium than basic medium Specifically, solubility of CUR at pH 1.2 and pH 6.8 were 7.230 Ỉ 0.35 and 12.6 23 Ỉ 3.54, respectively For this reason, most Table Formulation compositions of SDs Formulation Cur (mg) PEG 6000 (mg) HPMC 4000 (mg) HPMC (mg) PEO (mg) Ratio Mass (mg) Stirring time Combining method F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 30 30 30 30 30 30 30 30 30 30 120 240 120 120 120 120 240 240 240 240 – – – 60 – 120 120 180 120 180 – – 60 – – – – – – – – – – – 60 – – – – – 1:4 1:8 1:4:2 1:4:2 1:4:2 1:4:4 1:8:4 1:8:6 1:8:4 1:8:6 150 270 210 210 210 270 390 450 390 450 min min min min min I I I I I I I I II II 230 T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 dissolution release rate of CUR from SDs in the current studies in intestinal fluid (pH 6.8) was faster than that in gastric fluid (pH 1.2) and the percentage of pure CUR released in these media was under 5% in previous studies (Tran et al., 2015) Therefore, the improvement of dissolution rate in these conditions was discovered Fig shows the effect of polymer type on the CUR dissolution rate in pH 1.2 and pH 6.8 media In the first 10 min, the dissolution rates of F3 (HPMC 6) and F5 (PEO) tended to be greater than that of F4 (HPMC 4000) in both media However, the dissolution rate of F5 decreased after 20 min, and only a small percentage of drug (around 5–8%) was released from the formulation in the remainder of the experiment Meanwhile, after 30 min, F3 clearly had the highest drug release which (17.3% and 12.9% at pH 1.2 and pH 6.8, respectively) Unexpectedly, the dissolution profile of F3 exhibited a “spring-like” phenomenon (Tran et al., 2009) due to drug precipitation from 60 onwards in both media; in contrast, for F4, drug release increased continuously with increasing time in the media After h, F4 clearly had the highest drug release (17.7% and 18.6% at pH 1.2 and pH 6.8, respectively) Therefore, HPMC 4000 was selected for further study This result is interesting because drug release is expected to be slower in the polymer with higher viscosity In this study, HPMC 4000 has a higher viscosity than HPMC 6, which may have been an advantage of HPMC 4000 by preventing drug precipitation (Warren et al., 2010) Leuner and Dressman proved that one of the main influences on efficiency of a SD in increasing drug dissolution is the ratio between drug and carrier (Leuner and Dressman, 2000) The excessive drug amount in SD will tend to form more small crystals within the dispersion than maintain molecularly dispersed (Leuner and Dressman, 2000) On the other hand, the crystallinity of the drug will completely disappear in the case where the high percentage of carrier is used, which leads to a massive increase in solubility and dissolution rate of drug (Leuner and Dressman, 2000) Experiments were conducted with different CUR:PEG 600: HPMC 4000 ratios to determine which formulation most effectively increased drug dissolution Fig shows drug release from different formulations (CUR:PEG 600:HPMC 4000 ratios of 1:4, 1:8, 1:4:2, 1:4:4, 1:8:4, and 1:8:6, corresponding to samples F1, F2, F4, F6, F7, and F8, respectively) based on method I The highest percentage of drug release from F1, F2, F4, F6, F7, and F8 at pH 1.2 was 26.3%, 16.17%, 17.7%, 13.29%, 38.3%, and 29.31%, respectively Meanwhile, the highest percentage drug release at pH 6.8 were 18.53%, 17.07%, 18.6%, 18.93%, 42.83%, and 29.82%, respectively A much higher percentage of drug was released for F1 compared to F2, indicating that the higher polymer concentration resulted in a slower drug release For the higher amount of polymer, the formulation took longer to dissolve due to the longer water penetration process The percentages of drug released from F1 and F2 gradually decreased after 20 min, predominantly as a result of Fig Dissolution profiles of CUR from SDs of F3, F4 and F5 based on types of polymer as a function of time in gastric fluid (pH 1.2) (A) and intestinal fluid (pH 6.8) (B) Fig Dissolution profiles of CUR from SDs of F1, F2, F4 and F6 to F8 based on polymer ratio as a function of time in gastric fluid (pH 1.2) (A) and intestinal fluid (pH 6.8) (B) T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 precipitation, resulting in low dissolution rates after h (e.g., the percentage drug release of F1 and F2 after h were around 14.3% and 12.5% at both media respectively, decreasing from 1.3 to 1.8 fold as compared to their highest percentage drug release) However, the combination of PEG 6000 and HPMC 4000 in SDs gave good results F7 exhibited the highest percentage of drug release at pH 6.8 (about 42.83%; Fig 2B) Despite a little precipitation after 60 min, F7 was still far better in comparison to other formulations Nevertheless, increasing the amount of HPMC 4000 did not result in a higher percentage of drug release So, in method I F7 prepared at the ratio1:8:4 of CUR: PEG 6000: HPMC 4000 was chosen as the best SD formulation However, because the dissolution rates of SD formulations were still low (below 50%), a new method should be investigated to increase the percentage of drug release Dissolution and bioavailability of poorly water-soluble drugs can be enhanced by stabilizing the drugs in its amorphous state Permutation of introduction of carriers into the formulation may lead to modification of physicochemical properties of drug It was expected that the new approach would increase dissolution, and hence, bioavailability of CUR By applying the permutation of carriers, the percentage of drug release in method II was increased fold compared to method I While the percentages of drug release obtained using method I were 42.8% and 29.8% for F7 and F8, respectively, the percentage of drug release obtained using method II reached 82% and 62.6% for F9 and F10, respectively (see Fig 3A and B) These results suggested that method II produced more amorphous form than method I The influence of amorphous versus crystalline forms on drug dissolution would be explained clearer by FTIR and PXRD characterization in the following sections A large amount of HPMC 4000 in the formulation generally reduced the drug dissolution rate F9 and F10 dissolved better than F7 and F8, resulting in transparent solutions However, the fact that F10 seemed to have more sediment after h compared to F9 could explain why F9 dissolved better than F10 Probably redundant HPMC 4000 existed in solution could not fully swell It was also the reason why the formulation at ratio 1:8:6 (F8 and F10) always had a lower percentage drug release than the one at ratio 1:8:4 (F7 and F9), no matter what combining method was applied Finally, F9 was chosen to be the optimal model of the study In summary, in vitro dissolution tests indicated that PEG 6000 can be combined with other hydrophilic polymers to enhance the dissolution rates of poorly water-soluble drugs to prevent drug precipitation Interestingly, the combination of a poorly watersoluble drug with swellable polymers in PEG 6000-based SDs is a promising approach to improve dissolution rates However, the more interesting point was the step of the combination between PEG and drug or the combination between PEG and HPMC It played a critical factor to enhance drug dissolution release due to the modification of drug physicochemical properties The combination between PEG 6000 and HPMC should be conducted before adding drug (method II) for a double strength action of dissolving the drug and preventing the drug recrystallization The molecular dispersion of poorly water-soluble drugs in hydrophilic polymers of SDs would form a high surface area of drug and reduced particle size which promoted the dissolution enhancement and hence, led to increased bioavailability (Vasconcelos et al., 2007) Moreover, ratio among the components of the formulations was also very important Effects of those factors on drug dissolution profiles would be elucidated more through PXRD and FTIR studies 231 formulations on drug structure The XRD patterns of F7, F8, F9, and F10 are provided in Fig 4B to illustrate the effect of different combination methods on drug structure Amorphous state was indicated by the disappearance of distinctive peaks or a large reduction in number of characteristic peaks in diffractograms (Tran et al., 2008) The diffraction pattern of pure CUR showed numerous peaks, indicating the highly crystalline nature of the drug PM was obtained by thoroughly blending pure CUR, PEG 6000, and HPMC 4000 at a 1:8:4 ratio, which gave the highest drug release percentage The diffraction pattern of PM retained most of the characteristic peaks of pure CUR, PEG 6000, and HPMC 4000 However, compared with pure CUR, the peaks at 7.8, 12.2, 18.1, and 28.8 2u of PM were disappeared, resulting from the influence of amorphous form of HPMC 4000 For the PMs and SDs of F4 and F7, although most of the pure CUR peaks disappeared, the peaks at 19.1, 23.3, 26.1, 26.9, 36.2, 39.6, and 42.9 2u were still observed Nevertheless, the broad peaks at 13.5 2u disappeared in the PM spectra of F4 and F7 This broad peak might be affected by pure CUR or HPMC 4000; thus, its disappearance might indicate that CUR was well dispersed in PEG 6000, or that HPMC 4000 was almost completely swelled in PEG 6000, which would promote drug dissolution and hinder drug precipitation The characteristic peaks at 8.9, 10.5, 14.5, 14.9, and 17.2 2u were absent or reduced in 3.2 Effects of combination method and polymer ratio on drug crystallinity and molecular interaction The XRD patterns of X-ray pure CUR, PM, and SDs of F4, F7, and F8 are shown in Fig 4A to demonstrate effect of different Fig Dissolution profiles of curcumin from SDs of F7, F8, F9, and F10 based on combining method as a function of time in gastric fluid (pH 1.2) (A) and intestinal fluid (pH 6.8) (B) 232 T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 Fig (A) PXRD patterns of pure Cur PEG 6000, HPMC 4000, PM and SDs of F4, F7 and F8 in different ratio (B) PXRD patterns of SDs of F7, F8, F9 and F10 in different combining method magnitude in the F7 spectrum compared to in the F4 SD spectrum This indicated that F7 was more amorphous than F4, resulting in a higher dissolution rate Although the peaks at 26.1, 26.9, 32.5, 36.2, 39.6, and 42.9 2u were absent in the spectrum of F8 comparison with that of F7, a broad peak at 13.5 2u remained the in spectrum of F8 This indicated that F8 was influenced by the crystalline form of pure CUR or HPMC 4000 In the experiment, the amount of PEG 6000 in F8 was not enough to swell HPMC 4000 completely The excessive amount of HPMC 4000 influenced the ability of CUR to disperse in the carrier, resulting in the decreased dissolution rate Therefore, F8 had a lower dissolution rate than F7, even though its spectrum showed less peaks As illustrated in Fig 4B, the effect of the combination method on the physical structure of the formulation was evaluated The dissolution test results for the SDs of F7, F8, F9, and F10 (corresponding to 1:8:4 method I, 1:8:6 method I, 1:8:4 method II, and 1:8:6 method II, respectively) showed that the combination method could change the dissolution profile of CUR Although PM had the same ratio with F7 and F9, its diffraction pattern seemed to be similar with the ones of F8 and F10 This result was explained by the presence of HPMC 4000 or pure CUR in the physical structure The comparison of two methods at relative ratios showed that the disappearance or reduction of peaks was detected at 14.5, 14.9, 17.2, 32.5, 36.2, 39.6, and 42.9 2u in F9, suggesting the transformation into amorphous form from method I to method II Similarly, the decrease in intensity of peaks was observed at 13.5, 35.6, 36.2, and 39.6 2u in F10, supporting for the hypothesis mentioned above According to the study, increasing HPMC 4000 concentration did not enhance dissolution rate of CUR due to the lack of PEG 6000 amount for swelling HPMC 4000 Therefore, the ratio 1:8:6 always had lower dissolution rate compared to the ratio 1:8:4 regardless of any applied combining method In FTIR analysis, a specific chemical bond was indicated by the presence of a peak at a specific wavenumber The appearance of new peaks or a shift of existing peak represented a specific interaction among the materials (Liu and Bai, 2005) The FTIR spectra of pure CUR, PM, F4, F7, and F8 are shown in Fig 5A to demonstrate the effect of compositional ratio on CUR dissolution Bin et al (2013) suggested that the sharp band at around 3500 cmÀ1 and the broad peak centered at 3300 cmÀ1 in the crystalline spectrum are attributed to phenolic OH stretching The —OH group is indicated by a strong band around 2890 cmÀ1 The regions from 2700–3000 cmÀ1 in the spectra of pure CUR, HPMC 4000, PEG 6000, PM, and SDs exhibited peaks assigned to aliphatic C—H stretching (Bich et al., 2009) Strong bands at 1626 cmÀ1 in the spectra of pure CUR, PM, F4, F7, and F8 could be assigned to a predominantly mixed C¼C and C¼O character (Mohan et al., 2012) Moreover, the IR bands at 714 cmÀ1 in the spectra of these materials could be assigned to cis-C—H out of plane vibration of the aromatic ring (Mohan et al., 2012) No peak at 1430 cmÀ1 was observed in the spectrum of F8, revealing the lack of the in-plane bending vibration of olefinic C—H (Wan et al., 2012; Yadav et al., 2009) The disappearance of the peak at 1514 cmÀ1 in the spectrum of F7 indicated the absence of the highly mixed vibration of C¼O and C¼C (Wan et al., 2012; Yadav et al., 2009; Yallapu et al., 2010) The disappearance of this peak might be caused by the formation of intermolecular hydrogen bonds between the O—H groups of PEG 6000 and the C¼O groups of CUR, which would result in the increased solubility/dissolution of the drug (Yen et al., 2010) The comparison of these results with the dissolution profiles indicated that F7, which exhibited a better dissolution rate, could be applied for further study Fig 5B illustrates the influence of the combination method on the SDs of F7 to F10 In case of F9, the broad peak centered at 3300 cmÀ1 remained, while the sharp band at around 3500 cmÀ1 disappeared This peak might be affected by pure CUR or HPMC 4000 According to the preparation method and dissolution profile, HPMC 4000 firstly should be combined with PEG 6000 to have better swelling Consequently, the disappearance of phenol peak in the spectrum of F9 might be caused by hydrogen bond interactions In addition, the spectrum of F9 showed a new peak at 1714 cmÀ1, indicating a carbonyl groups and ketone groups in particular (John, 2000) CUR was present in at least two tautomeric forms including keto (a C¼O and an additional C—H bond) and enol (an O—H group T.N.-G Nguyen et al / International Journal of Pharmaceutics 484 (2015) 228–234 233 Fig (A) FTIR spectra of pure Cur PEG 6000, HPMC 4000, PM and SDs of F4, F7 and F8 in different ratio (B) FTIR spectra of curcumin, PEG 6000, HPMC 4000, PM and SDs of F7, F8, F9 and F10 in different combining method bound to a C¼C group) The delocalization of electron density in the p bond occurred due to the conjugation between the enol C¼C and the carbonyl group Moreover, the OH of the enol group could form a hydrogen bond with the oxygen of the nearby C¼O group These intramolecular hydrogen bonds are especially stabile when they form a six-membered ring (Janice, 2010) Therefore, the enol hydrogen ion (H+) is lost in the process of hydrogen bond formation Conclusion HPMC 4000 was demonstrated to be an effective swellable polymer in combination with PEG 6000 for enhancing drug dissolution in modified SDs Method II, in which PEG 6000 and HPMC 4000 were mixed before the drug was dispersed in the polymer mixture, was found to be the best combination method to achieve the aim of the study This combination method facilitated the swelling of HPMC 4000, resulting in good drug dispersion to change and maintain drug structure to amorphous form but also for promotion of some chemical interaction between the components, leading to increased drug dissolution The modified-SD would be an alternative approach to solve common problems of conventional SDs including drug precipitation and ineffective enhanced drug dissolution Acknowledgement We would like to thank International University, Vietnam National University, Ho Chi Minh City 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HPLC 2.2.7 Statistical analysis All data were presented as mean Ỉ standard deviation The statistical significance of the differences was determined using an analysis of variance (ANOVA) (P < 0.05... mixtures Int J Pharm 384, 60–66 Tran, T.T.-D., Tran, P.H.-L., Lee, B.-J., 2009 Dissolution- modulating mechanism of alkalizers and polymers in a nanoemulsifying solid dispersion containing ionizable and... poorly water-soluble drugs can be enhanced by stabilizing the drugs in its amorphous state Permutation of introduction of carriers into the formulation may lead to modification of physicochemical properties