臺灣博碩士論文加值系統

Aripiprazole（APZ）是一種用於治療思覺失調症之藥物，在過去的研究指出其相較於其他藥品具有較少之副作用，因此成為治療思覺失調症有吸引力的藥物選擇。思覺失調症被National Institutes of Health（NIH）定義為一種慢性和嚴重的精神疾病，需要長期治療。目前治療思覺失調症面臨最大的問題是患者服藥時的不依從性。在過去研究指出，相較於口服錠片，長效注射針劑可以改善患者不依從行為，降低疾病復發率。然而，給予APZ長效注射針劑時，因其達到最低有效濃度的時間較緩慢，必須在起始治療前14天連續給予口服錠片，以達最低有效濃度。因此本研究目的為開發Aripiprazole速放及緩釋處方合併使用之注射針劑，以持續釋放藥物。
本研究使用HPMC-E3或Pluronic® F68透過固體分散體技術之溶劑揮發法製備APZ速放及緩釋處方。在X-ray分析結果中，APZ：HPMC-E3 =
1：5（w/w）時，沒有觀察到明顯的繞射峰，呈現Amorphous form的狀態。在DSC分析結果顯示APZ透過固體分散製備過程使藥物晶型結構改變。從體外溶離結果觀察到最佳的緩釋處方比例為（APZ：HPMC-E3 = 1：0.5, w/w），將其藥物釋放結果與市售品進行溶離比對，差異因子 (f1)為5.01，相似因子 (f2)為66.58，具有與市售品相似之藥物釋放行為，而最佳的速放處方比例為APZ：HPMC-E3：Pluronic® F68 = 1：1：1, w/w/w)，其體外溶離試驗結果顯示在三十分鐘藥物釋放達80%。從體外溶離試驗也觀察到，在處方中添加Pluronic® F68可以增加藥物釋放。
綜合以上研究結果，本研究成功使用固體分散體技術同時製備出速放及緩釋處方。未來也會進一步將速放及緩釋處方合併，進行體外體內評估。

Aripiprazole (APZ) is an antipsychotic drug indicated for the treatment of patients with schizophrenia. It is an attractive choice for antipsychotic patients, as they have fewer side effects than other drugs in previous studies. Schizophrenia is defined by the National Institutes of Health (NIH) as a chronic and severe mental disorder that requires continuous long-term treatment. However, poor adherence to drug treatments has been recognized as a problem worldwide and may be the most challenging aspect of treating patients with schizophrenia. In previous studies, long-acting injectable formulations have potential advantages over tablet in improving compliance and thus reducing relapse rates. However, the slow onset of long-acting injectable formulations is a limitation that 14 consecutive days of oral administration is necessary to achieve therapeutic APZ concentrations during initiation of therapy. Thus, the aim of this study is to develop an injectable APZ delivery system in combination of instant and prolonged release profiles.
In this study, APZ instant release and sustained release formulations were prepared by solid dispersion with HPMC-E3 or Pluronic® F68 using solvent-based methods. The results of X-ray diffractometry show the APZ:HPMC-E3 (1:5, w/w) did not have distinct diffraction peaks indicating its lacked crystalline characteristics. The differential scanning calorimetry experiments indicate the crystal structure of APZ has been changed after solid dispersion process.
In terms of drug release, the optimal sustained release pattern was obtained from the composition of APZ:HPMC-E3 (1:0.5, w/w). Compared with commercial product, the difference factor (f1) is 5.01 and similarity factor (f2) is 66.58 suggest a high correlation. For optimal instant release formulation- APZ:HPMC-E3:Pluronic® F68 (1:1:1, w/w/w), 80% of APZ was released within 30 mins. Base on the in vitro dissolution test, we found that adding Pluronic® F68 in the formulation can 1, w/w/w), 80% of APZ was released within 30 mins. Base on the in vitro dissolution test, we found that adding Pluronic® F68 in the formulation can effectively enhance the drug release.
In conclusion, solid dispersion formulations were successfully prepared and demonstrated both instant release and sustained release profile. Combined instant release and sustained release formulations will be further evaluated the in vitro and in vivo behavior in the near future.

目錄
目錄 I
表目錄 IV
圖目錄 V
中文摘要 VIII
Abstract IX
第一章 緒論 1
1、思覺失調症之簡介 2
1.1 思覺失調症之介紹 2
1.1.1 思覺失調症疾病特徵 2
1.1.2 思覺失調症疾病之假說 3
1.2 治療思覺失調症藥物之臨床應用 5
1.3 思覺失調症治療之困境 8
2、模式藥物–Aripiprazole 13
2.1 物化性質 13
2.2 藥理機轉 13
2.3 已上市產品 14
3、固體分散體 17
3.1 固體分散體分類 19
3.2 固體分散體之製備方法 23
4、研究動機與目的 27
第二章 實驗材料與方法 29
2.1 實驗材料 29
2.2 實驗方法 30
2.2.1 Aripiprazole注射劑型之製備及處方開發 30
2.2.1.1 賦形劑–Hydroxypropyl methylcellulose（HPMC） 31
2.2.1.2 非離子型界面活性劑–Pluronic® 34
2.2.2 Aripiprazole注射劑型之物性評估 36
2.2.2.1 形態學研究 36
2.2.2.2 X-ray powder diffraction analysis（XRPD） 36
2.2.2.3 Differential scanning calorimetry（DSC）analysis 37
2.2.2.4 Fourier transform infrared spectrometer（FTIR） 38
2.2.3 Aripiprazole分析方法建立及其確效 39
2.2.3.1 Aripiprazole溶液之分析方法建立及其確效 39
2.2.4 藥物含量分析 41
2.2.5 體外藥物釋放試驗（Dissolution test） 42
2.2.6 體內藥物動力學實驗（Pharmacokinetics test） 45
第三章 結果與討論 47
3.1 Aripiprazole注射劑型之製備及處方開發 47
3.2 Aripiprazole注射劑型之物性評估 49
3.2.1 外觀形態學 49
3.2.2 X-ray powder diffraction analysis（XRPD） 56
3.2.3 Differential scanning calorimetry（DSC）analysis 67
3.2.3 Fourier transform infrared spectrometer（FTIR） 72
3.3 Aripiprazole分析方法確立 75
3.3.1 Aripiprazole溶液之分析方法確效 75
3.4 藥物含量分析 79
3.5 體外藥物釋放試驗（Dissolution test） 80
第四章 結論 84
第五章 參考文獻 85
附錄一、動物實驗申請表暨同意書 92

表目錄
Table 1. The characteristic symptoms of schizophrenia. 3
Table 2. First- and second-generation antipsychotics and D2 antagonism [16]. 6
Table 3. The advantages of long-acting injectable antipsychotics [5]. 10
Table 4. Summary of second-generation long-acting injectable antipsychotics [6]. 11
Table 5. Commercial product of Aripiprazole. 15
Table 6. Summary of pharmacokinetic parameters of aripiprazole [33]. 16
Table 7. Examples of FDA-approved products that use solid dispersions technologies. 17
Table 8. List of drugs investigated for solid dispersions [45]. 26
Table 9. Aripiprazole instant release and sustained release formulations. 30
Table 10. USP specifications for different types of HPMC, classified according to their degree of methoxy- and hydroxypropoxy-substitution [58]. 32
Table 11. HPMC commercial grade with respective viscosity [60]. 32
Table 12. Dissolution method of aripiprazole. 43
Table 13. Aripiprazole instant release and sustained release formulations. 48
Table 14. The 2 theta angles of different samples. 65
Table 15. The melting point of different samples. 70
Table 16. Intraday precision and accuracy (n=6) of aripiprazole solution. 78
Table 17. Interday precision and accuracy (n=6) of aripiprazole solution. 78
Table 18. The assay of aripiprazole in solid dispersion formulations. 79
Table 19. f1 and f2 values for aripiprazole release in 0.25% SDS solution. 83


圖目錄
Figure 1. Dopamine pathways in the brain [15]. 4
Figure 2. Cartoon illustrating how the proposed D2 dopamine partial agonist mechanism works in third generation antipsychotics. 7
Figure 3. Median aripiprazole concentrations vs. day for the first 2 doses, stratified by dosing initiation scheme. 12
Figure 4. Chemical structure of aripiprazole [28]. 13
Figure 5. Structure-based classification of solid dispersion. (Dark circles indicate solute atoms or molecules, while open circles indicate solvent atoms or molecules) [41]. 20
Figure 6. Phase diagram for a eutectic system [42]. 20
Figure 7. Carrier-Based classification of Solid Dispersion [45]. 22
Figure 8. Manufacturing methods of solid dispersion [45]. 25
Figure 9. Schematic presentation of a twin-screw extruder set-up [57]. 25
Figure 10. Chemical structure of HPMC. The substituent R represents either a –CH3, or a –CH2CH(CH3)OH group, or a hydrogen atom [58]. 31
Figure 11. Molecular structure of a Pluronic® triblock copolymer [61]. 35
Figure 12. Component of Pluronic® series products.（colour code: physical state of copolymers under ambient conditions: green = liquid; red = paste; orange = flake）[61]. 35
Figure 13. Scheme to derivate the Bragg law. X-rays (arrows) are reflected by crystallographic planes separated by a distance d [65]. 37
Figure 14. Surface morphology of (A) APZ, (B) APZ Product, and (C) AHP 1-0-0. Magnification 3000x. 51
Figure 15. Surface morphology of (A) APZ, (B) HPMC-E3, (C) Physical mixture of AHP 1-5-0, (D) AHP 1-0.5-0, (E) AHP 1-1-0, and (F) AHP 1-5-0. Magnification 300x. 52
Figure 16. Surface morphology of (A) APZ, (B) HPMC-E3, (C) Physical mixture of AHP 1-5-0, (D) AHP 1-0.5-0, (E) AHP 1-1-0, and (F) AHP 1-5-0. Magnification 3000x. 53
Figure 17. Surface morphology of (A) APZ, (B) HPMC-E3, (C) Pluronic® F68, (D) Physical mixture of AHP 1-1-1, (E) AHP 1-0.25-0.05, (F) AHP 1-0.25-0.25, (G) AHP 1-0.5-0.5, and (H) AHP 1-1-1. Magnification 300x. 54
Figure 18. Surface morphology of (A) APZ, (B) HPMC-E3, (C) Pluronic® F68, (D) Physical mixture of AHP 1-1-1, (E) AHP 1-0.25-0.05, (F) AHP 1-0.25-0.25, (G) AHP 1-0.5-0.5, and (H) AHP 1-1-1. Magnification 3000x. 55
Figure 19. X-ray diffraction pattern of APZ, APZ Product, HPMC-E3, AHP 1-5-0 (pm), AHP 1-0-0, 1-0.5-0, 1-1-0, and 1-5-0. 58
Figure 20. X-ray diffraction pattern of APZ, APZ Product, HPMC-E3, F68, AHP 1-1-1 (pm), AHP 1-0-0, 1-0.25-0.05, 1-0.25-0.25, 1-0.5-0.5, and 1-1-1. 59
Figure 21. X-ray diffraction pattern of Hydrate A. 60
Figure 22. X-ray diffraction pattern of Anhydrous Crystals B. 60
Figure 23. X-ray diffraction pattern of Anhydrous Crystals C. 61
Figure 24. X-ray diffraction pattern of Anhydrous Crystals D. 61
Figure 25. X-ray diffraction pattern of Anhydrous Crystals E. 62
Figure 26. X-ray diffraction pattern of Anhydrous Crystals F. 62
Figure 27. X-ray diffraction pattern of Anhydrous Crystals G. 63
Figure 28. Crystal form Ⅰ of aripiprazole in CCDC. 63
Figure 29. Crystal form Ⅱ of aripiprazole in CCDC. 64
Figure 30. Crystal form Ⅲ of aripiprazole in CCDC. 64
Figure 31. Crystal form Ⅳ of aripiprazole in CCDC. 64
Figure 32. DSC thermograms of APZ, APZ Product, HPMC-E3, AHP 1-5-0 (pm), AHP 1-0-0, 1-0.5-0, 1-1-0, and 1-5-0. 69
Figure 33. DSC thermograms of APZ, APZ Product, HPMC-E3, F68, AHP 1-1-1 (pm), AHP 1-0-0, 1-0.25-0.05, 1-0.25-0.25, 1-0.5-0.5, and 1-1-1. 69
Figure 34. FTIR spectra of APZ, APZ Product, HPMC-E3, AHP 1-5-0 (pm), AHP 1-0-0, 1-0.5-0, 1-1-0, and 1-5-0. 73
Figure 35. FTIR spectra of APZ, APZ Product, HPMC-E3, F68, AHP 1-1-1 (pm), AHP 1-0-0, 1-0.25-0.05, 1-0.25-0.25, 1-0.5-0.5, and 1-1-1. 74
Figure 36. HPLC chromatogram of aripiprazole. 76
Figure 37. Intraday calibration curve of aripiprazole. 77
Figure 38. Interday calibration curve of aripiprazole. 77
Figure 39. In vitro drug release profile of APZ Product, AHP 1-0-0, AHP 1-0.5-0, 1-1-0, and 1-5-0 (n=3). 82
Figure 40. In vitro drug release profile of APZ Product, AHP 1-0-0, AHP 1-0.25-0.05, AHP 1-0.25-0.25, 1-0.5-0.5, and 1-1-1 (n=3). 82
Figure 41. In vitro drug release profile of AHP 1-0.5-0, 1-0.5-0.5, 1-1-0, and 1-1-1 (n=3). 83

第五章參考文獻
[1] C.-W. Park, H.-J. Lee, D.-W. Oh, J.-H. Kang, C.-S. Han, D.-W. Kim, Preparation and in vitro/in vivo evaluation of PLGA microspheres containing norquetiapine for long-acting injection, Drug design, development and therapy 12 (2018) 711.
[2] C.-W. Hsu, S.-Y. Lee, L.-J. Wang, Gender differences in the prevalence, comorbidities and antipsychotic prescription of early-onset schizophrenia: a nationwide population-based study in Taiwan, European child & adolescent psychiatry 28(6) (2019) 759-767.
[3] K. Higashi, G. Medic, K.J. Littlewood, T. Diez, O. Granström, M. De Hert, Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review, Therapeutic advances in psychopharmacology 3(4) (2013) 200-218.
[4] E. Achilla, P. McCrone, The cost effectiveness of long-acting/extended-release antipsychotics for the treatment of schizophrenia, Applied health economics and health policy 11(2) (2013) 95-106.
[5] S. Brissos, M.R. Veguilla, D. Taylor, V. Balanzá-Martinez, The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal, Therapeutic advances in psychopharmacology 4(5) (2014) 198-219.
[6] M.W. Jann, S.R. Penzak, Long-acting injectable second-generation antipsychotics: an update and comparison between agents, CNS drugs (2018) 1-17.
[7] Center for Drug Evaluation and Research. Application Number: 202971Orig1s000 Clinical Pharmacology and Biopharmaceutics Review(s) Silver Spring: Food and Drug Administration, 2012.
[8] N.C. Andreasen, S. Olsen, Negative v positive schizophrenia: Definition and validation, Archives of general psychiatry 39(7) (1982) 789-794.
[9] N.C. Andreasen, M. Flaum, Schizophrenia: the characteristic symptoms, Schizophrenia bulletin 17(1) (1991) 27-49.
[10] E.H. Simpson, C. Kellendonk, E. Kandel, A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia, Neuron 65(5) (2010) 585-596.
[11] A. Yang, S.-J. Tsai, New targets for schizophrenia treatment beyond the dopamine hypothesis, International journal of molecular sciences 18(8) (2017) 1689.
[12] S.M. Stahl, Essential psychopharmacology of antipsychotics and mood stabilizers, Cambridge University Press2002.
[13] S. Kapur, Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia, American journal of Psychiatry 160(1) (2003) 13-23.
[14] D.C. Goff, J.T. Coyle, The emerging role of glutamate in the pathophysiology and treatment of schizophrenia, American Journal of Psychiatry 158(9) (2001) 1367-1377.
[15] S.M. Stahl, S.M. Stahl, Stahl''s essential psychopharmacology: neuroscientific basis and practical applications, Cambridge university press2013.
[16] N. Divac, M. Prostran, I. Jakovcevski, N. Cerovac, Second-generation antipsychotics and extrapyramidal adverse effects, BioMed research international 2014 (2014).
[17] C. Bushe, M. Shaw, R.C. Peveler, A review of the association between antipsychotic use and hyperprolactinaemia, Journal of Psychopharmacology 22(2_suppl) (2008) 46-55.
[18] H.Y. Meltzer, Update on typical and atypical antipsychotic drugs, Annual review of medicine 64 (2013) 393-406.
[19] R. Tandon, Antipsychotics in the treatment of schizophrenia: an overview, The Journal of clinical psychiatry 72 (2011) 4-8.
[20] R.B. Mailman, V. Murthy, Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?, Current pharmaceutical design 16(5) (2010) 488-501.
[21] J. Zhao, L. Wang, C. Fan, K. Yu, X. Liu, X. Zhao, D. Wang, W. Liu, Z. Su, F. Sun, Development of near zero-order release PLGA-based microspheres of a novel antipsychotic, International journal of pharmaceutics 516(1-2) (2017) 32-38.
[22] F.J. Charlson, A.J. Ferrari, D.F. Santomauro, S. Diminic, E. Stockings, J.G. Scott, J.J. McGrath, H.A. Whiteford, Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016, Schizophrenia bulletin 44(6) (2018) 1195-1203.
[23] H.Y. Chong, S.L. Teoh, D.B.-C. Wu, S. Kotirum, C.-F. Chiou, N. Chaiyakunapruk, Global economic burden of schizophrenia: a systematic review, Neuropsychiatric disease and treatment 12 (2016) 357.
[24] W.V. Bobo, R.C. Shelton, Risperidone long-acting injectable (Risperdal Consta®) for maintenance treatment in patients with bipolar disorder, Expert review of neurotherapeutics 10(11) (2010) 1637-1658.

[25] S. Heres, S. Kraemer, R.F. Bergstrom, H.C. Detke, Pharmacokinetics of olanzapine long-acting injection: the clinical perspective, International clinical psychopharmacology 29(6) (2014) 299.
[26] K. Sedky, R. Nazir, J.-P. Lindenmayer, S. Lippmann, Paliperidone palmitate: once-monthly treatment option for schizophrenia, Current Psychiatry 9(3) (2010) 48-50.
[27] M. Zumárraga, A. Arrue, O. Olivas, W. Dávila, Aripiprazole reverses paliperidone-induced hyperprolactinemia, Actas Esp Psiquiatr 40(5) (2012) 90-2.
[28] T.S. Harrison, C.M. Perry, Aripiprazole, Drugs 64(15) (2004) 1715-1736.
[29] K.A. Lentz, M. Quitko, D.G. Morgan, J.E. Grace Jr, C. Gleason, P.H. Marathe, Development and validation of a preclinical food effect model, Journal of pharmaceutical sciences 96(2) (2007) 459-472.
[30] M. Łaszcz, A. Witkowska, Studies of phase transitions in the aripiprazole solid dosage form, Journal of pharmaceutical and biomedical analysis 117 (2016) 298-303.
[31] A.B. Casey, C.E. Canal, Classics in chemical neuroscience: aripiprazole, ACS chemical neuroscience 8(6) (2017) 1135-1146.
[32] M. Rohde, A.E. Håkansson, K.G. Jensen, H. Pedersen, T. Dige, R. Holm, Biological conversion of aripiprazole lauroxil− An N-acyloxymethyl aripiprazole prodrug, Results in pharma sciences 4 (2014) 19-25.
[33] K. Hebbrecht, M. Morrens, H. Neels, L. Roosens, B.G. Sabbe, Pharmacokinetic evaluation of the aripiprazole (once-monthly) injection for the treatment of bipolar disorder, Expert opinion on drug metabolism & toxicology 14(10) (2018) 999-1005.
[34] L.A. Nikghalb, G. Singh, G. Singh, K.F. Kahkeshan, Solid Dispersion: Methods and Polymers to increase the solubility of poorly soluble drugs, Journal of Applied Pharmaceutical Science 2(10) (2012) 170-175.
[35] D.N. Bikiaris, Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs, Expert opinion on drug delivery 8(11) (2011) 1501-1519.
[36] Y. He, C. Ho, Amorphous solid dispersions: utilization and challenges in drug discovery and development, Journal of Pharmaceutical Sciences 104(10) (2015) 3237-3258.
[37] A.C. Rumondor, S.S. Dhareshwar, F. Kesisoglou, Amorphous solid dispersions or prodrugs: complementary strategies to increase drug absorption, Journal of pharmaceutical sciences 105(9) (2016) 2498-2508.
[38] T. Vasconcelos, S. Marques, J. das Neves, B. Sarmento, Amorphous solid dispersions: Rational selection of a manufacturing process, Advanced drug delivery reviews 100 (2016) 85-101.
[39] S.V. Jermain, C. Brough, R.O. Williams III, Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery–an update, International journal of pharmaceutics 535(1-2) (2018) 379-392.
[40] C.A. McKelvey, F. Kesisoglou, Enabling an HCV Treatment Revolution and the Frontiers of Solid Solution Formulation, Journal of pharmaceutical sciences 108(1) (2019) 50-57.
[41] S.B. Teja, S.P. Patil, G. Shete, S. Patel, A.K. Bansal, Drug-excipient behavior in polymeric amorphous solid dispersions, Journal of Excipients and Food Chemicals 4(3) (2016).
[42] C. Leuner, J. Dressman, Improving drug solubility for oral delivery using solid dispersions, European journal of Pharmaceutics and Biopharmaceutics 50(1) (2000) 47-60.
[43] W.L. Chiou, S. Riegelman, Pharmaceutical applications of solid dispersion systems, Journal of pharmaceutical sciences 60(9) (1971) 1281-1302.
[44] H. Konno, T. Handa, D.E. Alonzo, L.S. Taylor, Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine, European journal of pharmaceutics and biopharmaceutics 70(2) (2008) 493-499.
[45] P. Tran, Y.-C. Pyo, D.-H. Kim, S.-E. Lee, J.-K. Kim, J.-S. Park, Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs, Pharmaceutics 11(3) (2019) 132.
[46] K. Sekiguchi, N. Obi, Studies on Absorption of Eutectic Mixture. I. A Comparison of the Behavior of Eutectic Mixture of Sulfathiazole and that of Ordinary Sulfathiazole in Man, Chemical and Pharmaceutical Bulletin 9(11) (1961) 866-872.
[47] V.G. Kadajji, G.V. Betageri, Water soluble polymers for pharmaceutical applications, Polymers 3(4) (2011) 1972-2009.
[48] P. Franco, E. Reverchon, I. De Marco, PVP/ketoprofen coprecipitation using supercritical antisolvent process, Powder Technology 340 (2018) 1-7.
[49] E. Jafari, Preparation, characterization and dissolution of solid dispersion of diclofenac sodium using Eudragit E-100, Journal of Applied Pharmaceutical Science 3(8) (2013) 167.


[50] Z. Sun, H. Zhang, H. He, X. Zhang, Q. Wang, K. Li, Z. He, Cooperative effect of polyvinylpyrrolidone and HPMC E5 on dissolution and bioavailability of nimodipine solid dispersions and tablets, Asian Journal of Pharmaceutical Sciences (2018).
[51] T. Panda, D. Das, L. Panigrahi, Formulation development of solid dispersions of bosentan using Gelucire 50/13 and Poloxamer 188, J. Appl. Pharm. Sci 6 (2016) 027-033.
[52] T.K. Giri, K. Kumar, A. Alexander, H. Badwaik, D.K. Tripathi, A novel and alternative approach to controlled release drug delivery system based on solid dispersion technique, Bulletin of Faculty of Pharmacy, Cairo University 50(2) (2012) 147-159.
[53] N.V. Dhandapani, A.A. El-Gied, Solid dispersions of cefixime using β-cyclodextrin: Characterization and in vitro evaluation, Int. J. Pharmacol. Pharm. Sci 10 (2016) 1523-1527.
[54] J. Breitenbach, Melt extrusion: from process to drug delivery technology, European journal of pharmaceutics and biopharmaceutics 54(2) (2002) 107-117.
[55] C.L.-N. Vo, C. Park, B.-J. Lee, Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs, European journal of pharmaceutics and biopharmaceutics 85(3) (2013) 799-813.
[56] N. Fan, Z. He, P. Ma, X. Wang, C. Li, J. Sun, Y. Sun, J. Li, Impact of HPMC on inhibiting crystallization and improving permeability of curcumin amorphous solid dispersions, Carbohydrate polymers 181 (2018) 543-550.
[57] S. Huang, R.O. Williams, Effects of the preparation process on the properties of amorphous solid dispersions, AAPS PharmSciTech 19(5) (2018) 1971-1984.
[58] J. Siepmann, N. Peppas, Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC), Advanced drug delivery reviews 64 (2012) 163-174.
[59] W. Huichao, D. Shouying, L. Yang, L. Ying, W. Di, The application of biomedical polymer material hydroxy propyl methyl cellulose (HPMC) in pharmaceutical preparations, Journal of Chemical and Pharmaceutical Research 6(5) (2014) 155-160.
[60] D. Phadtare, G. Phadtare, M. Asawat, Hypromellose–a choice of polymer in extended release tablet formulation, World J Pharm Pharm Sci 3 (2014) 551-566.
[61] A. Pitto-Barry, N.P. Barry, Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances, Polymer Chemistry 5(10) (2014) 3291-3297.

[62] M. Kurahashi, K. Kanamori, K. Takeda, H. Kaji, K. Nakanishi, Role of block copolymer surfactant on the pore formation in methylsilsesquioxane aerogel systems, RSC Advances 2(18) (2012) 7166-7173.
[63] W. Ali, A.C. Williams, C.F. Rawlinson, Stochiometrically governed molecular interactions in drug: poloxamer solid dispersions, International journal of pharmaceutics 391(1-2) (2010) 162-168.
[64] C.K. Song, I.-S. Yoon, D.-D. Kim, Poloxamer-based solid dispersions for oral delivery of docetaxel: Differential effects of F68 and P85 on oral docetaxel bioavailability, International journal of pharmaceutics 507(1-2) (2016) 102-108.
[65] M.C. García-Gutiérrez, A. Nogales Ruiz, J.J. Hernández, D.R. Rueda, T.A. Ezquerra, X-ray scattering applied to the analysis of carbon nanotubes, polymers and nanocomposites, (2007).
[66] Y. Xu, X. Liu, R. Lian, S. Zheng, Z. Yin, Y. Lu, W. Wu, Enhanced dissolution and oral bioavailability of aripiprazole nanosuspensions prepared by nanoprecipitation/homogenization based on acid–base neutralization, International journal of pharmaceutics 438(1-2) (2012) 287-295.
[67] A. Prior, P. Frutos, C. Correa, Comparison of dissolution profiles: current guidelines, VI Congreso SEFIG y, 2010, pp. 507-509.
[68] B.S. Zolnik, D.J. Burgess, Evaluation of in vivo–in vitro release of dexamethasone from PLGA microspheres, Journal of controlled release 127(2) (2008) 137-145.
[69] T. Bando, S. Aoki, J. Kawasaki, M. Ishigami, Y. Taniguchi, T. Yabuuchi, K. Fujimoto, Y. Nishioka, N. Kobayashi, T. Fujimura, Low hygroscopic aripiprazole drug substance and processes for the preparation thereof, Google Patents, 2015.
[70] R. Bayón, E. Rojas, Feasibility study of D-mannitol as phase change material for thermal storage, AIMS Energy 5(3) (2017) 404-424.
[71] A.M. Nik, S. Langmaid, A.J. Wright, Nonionic surfactant and interfacial structure impact crystallinity and stability of β-carotene loaded lipid nanodispersions, Journal of agricultural and food chemistry 60(16) (2012) 4126-4135.
[72] S. YADAV, M. VEENA, M. SRINIVAS, SOLID DISPERSION TECHNIQUE TO ENHANCE THE SOLUBILITY AND DISSOLUTION RATE OF ARIPIPRAZOLE BY FUSION METHOD, (2016).
[73] S.D. Javeer, P.D. Amin, Solubility and dissolution enhancement of HPMC‑based solid dispersions of carbamazepine by hot‑melt extrusion technique, Asian Journal of Pharmaceutics (AJP): Free full text articles from Asian J Pharm 8(2) (2014).
[74] G. MAGHRABY, A. ALOMRANI, Synergistic enhancement of itraconazole dissolution by ternary system formation with pluronic F68 and hydroxypropylmethylcellulose, Scientia Pharmaceutica 77(2) (2009) 401-418.
[75] X. He, L. Pei, H.H. Tong, Y. Zheng, Comparison of spray freeze drying and the solvent evaporation method for preparing solid dispersions of baicalein with Pluronic F68 to improve dissolution and oral bioavailability, AAPS pharmscitech 12(1) (2011) 104-113.