Skip to main content

Advertisement

SpringerLink
Log in

Continuous Manufacturing and Molecular Modeling of Pharmaceutical Amorphous Solid Dispersions

  • Review Article
  • Advancements in Amorphous Solid Dispersions to Improve Bioavailability
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Amorphous solid dispersions enhance solubility and oral bioavailability of poorly water-soluble drugs. The escalating number of drugs with poor aqueous solubility, poor dissolution, and poor oral bioavailability is an unresolved problem that requires adequate interventions. This review article highlights recent solubility and bioavailability enhancement advances using amorphous solid dispersions (ASDs). The review also highlights the mechanism of enhanced dissolution and the challenges faced by ASD-based products, such as stability and scale-up. The role of process analytical technology (PAT) supporting continuous manufacturing is highlighted. Accurately predicting interactions between the drug and polymeric carrier requires long experimental screening methods, and this is a space where computational tools hold significant potential. Recent advancements in data science, computational tools, and easy access to high-end computation power are set to accelerate ASD-based research. Hence, particular emphasis has been given to molecular modeling techniques that can address some of the unsolved questions related to ASDs. With the advancement in PAT tools and artificial intelligence, there is an increasing interest in the continuous manufacturing of pharmaceuticals. ASDs are a suitable option for continuous manufacturing, as production of a drug product from an ASD by direct compression is a reality, where the addition of multiple excipients is easy to avoid. Significant attention is necessary for ongoing clinical studies based on ASDs, which is paving the way for the approval of many new ASDs and their introduction into the market.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Van den Mooter GJDDTT. The use of amorphous solid dispersions: a formulation strategy to overcome poor solubility and dissolution rate. Drug Disc Today. 2012;9(2):e79–85.

    Article  Google Scholar 

  2. Ojo AT, Ma C, Lee PIJIJoP. Elucidating the effect of crystallization on drug release from amorphous solid dispersions in soluble and insoluble carriers. Int J Pharm. 2020;591:120005.

  3. Benet LZJJops. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J Pharm Sci. 2013;102(1):34–42.

    Article  Google Scholar 

  4. Fahr A, Liu XJEoodd. Drug delivery strategies for poorly water-soluble drugs. Expert opinion on drug delivery. 2007;4(4):403–16.

    Article  CAS  PubMed  Google Scholar 

  5. Wilson VR, Lou X, Osterling DJ, Stolarik DF, Jenkins GJ, Nichols BL, et al. Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: Investigation of relationships between polymer structure and performance. Scientific reports. 2020;10(1):1–12.

    Article  CAS  Google Scholar 

  6. Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue SJIjop. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  7. Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Järvinen T, et al. Prodrugs: design and clinical applications. Natures. 2008;7(3):255–70.

    CAS  Google Scholar 

  8. Loftsson T, Duchene DJIjop. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329(1–2):1–11.

    Article  CAS  PubMed  Google Scholar 

  9. Rabinow BEJNrDd. Nanosuspensions in drug delivery. Natures. 2004;3(9):785–96.

    Google Scholar 

  10. Berge SM, Bighley LD. Monkhouse DCJJops. Pharmaceutical salts. J Pharm Sci. 1977;66(1):1–19.

    Article  CAS  PubMed  Google Scholar 

  11. Lavasanifar A, Samuel J, Kwon GSJAddr. Poly (ethylene oxide)-block-poly (L-amino acid) micelles for drug delivery. Adv Drug Delivery Rev. 2002;54(2):169–90.

    Article  CAS  Google Scholar 

  12. Fatouros DG, Deen GR, Arleth L, Bergenstahl B, Nielsen FS, Pedersen JS, et al. Structural development of self nano emulsifying drug delivery systems (SNEDDS) during in vitro lipid digestion monitored by small-angle X-ray scattering. Pharmaceutical research. 2007;24(10):1844–53.

    Article  CAS  PubMed  Google Scholar 

  13. Potta SG, Minemi S, Nukala RK, Peinado C, Lamprou DA, Urquhart A, et al. Development of solid lipid nanoparticles for enhanced solubility of poorly soluble drugs. J Biomed Nanotech. 2010;6(6):634–40.

    Article  CAS  Google Scholar 

  14. Patel VR, Agrawal YJJoapt, research. Nanosuspension: an approach to enhance solubility of drugs. J Advanc Pharma Tech 2011;2(2):81.

  15. Gao P, Shi YJTAj. Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs. AAPS journal. 2012;14(4):703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gala UH, Miller DA, Su Y, Spangenberg A, Williams ROB 3rd. The effect of drug loading on the properties of abiraterone-hydroxypropyl beta cyclodextrin solid dispersions processed by solvent free KinetiSol(R) technology. Eur J Pharm Biopharm. 2021;165:52–65.

    Article  CAS  PubMed  Google Scholar 

  17. Maple JR, Dinur U. Hagler ATJPotNAoS. Derivation of force fields for molecular mechanics and dynamics from ab initio energy surfaces. Proceedings of the National Academy of Sciences. 1988;85(15):5350–4.

    Article  CAS  Google Scholar 

  18. Jang D-J, Sim T, Oh EJD. pharmacy i. Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption. J Drug develop. 2013;39(7):1133–41.

    CAS  Google Scholar 

  19. Ellenberger DJ, Miller DA, Williams ROJAP. Expanding the application and formulation space of amorphous solid dispersions with KinetiSol®: a review. AAPS Pharmscitech. 2018;19(5):1933–56.

    Article  CAS  PubMed  Google Scholar 

  20. Wu JX, Yang M, van den Berg F, Pajander J, Rades T, Rantanen JJEjops. Influence of solvent evaporation rate and formulation factors on solid dispersion physical stability. Eur J Pharm Sci. 2011;44(5):610–20.

    Article  CAS  PubMed  Google Scholar 

  21. Mosquera-Giraldo LI, Borca CH, Meng X, Edgar KJ, Slipchenko LV, Taylor LSJB. Mechanistic design of chemically diverse polymers with applications in oral drug delivery. Biomacromolecules. 2016;17(11):3659–71.

    Article  CAS  PubMed  Google Scholar 

  22. Indulkar AS, Lou X, Zhang GGZ, Taylor LS. Insights into the dissolution mechanism of ritonavir-copovidone amorphous solid dispersions: importance of congruent release for enhanced performance. Mol Pharm. 2019;16(3):1327–39.

    Article  CAS  PubMed  Google Scholar 

  23. Mosquera-Giraldo LI, Li N, Wilson VR, Nichols BL, Edgar KJ, Taylor LSJMP. Influence of polymer and drug loading on the release profile and membrane transport of telaprevir. Mol Pharm. 2018;15(4):1700–13.

    Article  CAS  PubMed  Google Scholar 

  24. Martínez LM, Videa M, Sosa NG, Ramírez JH, Castro SJM. Long-term stability of new co-amorphous drug binary systems: Study of glass transitions as a function of composition and shelf time. Molecules. 2016;21(12):1712.

    Article  PubMed Central  Google Scholar 

  25. Van den Mooter G, Weuts I, De Ridder T, Blaton NJIjop. Evaluation of Inutec SP1 as a new carrier in the formulation of solid dispersions for poorly soluble drugs. Int J Pharm. 2006;316(1–2):1–6.

    Article  PubMed  Google Scholar 

  26. Medarević D, Djuriš J, Barmpalexis P, Kachrimanis K, Ibrić SJP. Analytical and computational methods for the estimation of drug-polymer solubility and miscibility in solid dispersions development. Pharmaceutics. 2019;11(8):372.

    Article  PubMed Central  Google Scholar 

  27. DeBoyace K, Wildfong PLJJoPS. The application of modeling and prediction to the formation and stability of amorphous solid dispersions. J Pharm Sci. 2018;107(1):57–74.

    Article  CAS  PubMed  Google Scholar 

  28. Mendonsa N, Almutairy B, Kallakunta V, Sarabu S, Thipsay P, Bandari S. Manufacturing strategies to develop amorphous solid dispersions: an overview. J Drug Deliv Sci Technol. 2020;55(101459):2019.

    Google Scholar 

  29. Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Kumar Battu S, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug development industrial pharmacy. 2007;33(9):909–26.

    Article  CAS  PubMed  Google Scholar 

  30. Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, et al. Pharmaceutical applications of hot-melt extrusion: Part II. J Drug Develop. 2007;33(10):1043–57.

    CAS  Google Scholar 

  31. Li N, Cape JL, Mankani BR, Zemlyanov DY, Shepard KB, Morgen MM, et al. Water-induced phase separation of spray-dried amorphous solid dispersions. Mol Pharm. 2020;17(10):4004–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Obaidat RM, Tashtoush BM, Awad AA, Al Bustami RTJAP. Using supercritical fluid technology (SFT) in preparation of tacrolimus solid dispersions. AAPS PharmSciTech. 2017;18(2):481–93.

    Article  CAS  PubMed  Google Scholar 

  33. Fülöp G, Balogh A, Farkas B, Farkas A, Szabó B, Démuth B, et al. Homogenization of amorphous solid dispersions prepared by electrospinning in low-dose tablet formulation. Pharmaceutics. 2018;10(3):114.

    Article  PubMed Central  Google Scholar 

  34. Burcham CL, Florence AJ, Johnson MDJAroc, engineering b. Continuous manufacturing in pharmaceutical process development and manufacturing. Annual review of chemical biomolecular engineering 2018;9:253–281.

  35. Lapuk S, Mukhametzyanov T, Schick C, Gerasimov AJIJoP. Kinetic stability of amorphous dipyridamole: a fast scanning calorimetry investigation. Int J Pharm. 2020;574:118890.

  36. Newman A, Zografi GJAP. Commentary: considerations in the measurement of glass transition temperatures of pharmaceutical amorphous solids. AAPS PharmSciTech. 2020;21(1):1–13.

    Article  Google Scholar 

  37. Neilly JP, Yin L, Leonard S-E, Kenis PJ, Danzer GD, Pawate ASJJoPS. Quantitative measures of crystalline fenofibrate in amorphous solid dispersion formulations by X-ray microscopy. J Pharm Sci. 2020;109(10):3078–85.

    Article  CAS  PubMed  Google Scholar 

  38. Jha DK, Shah DS, Amin PDJIJoP. Thermodynamic aspects of the preparation of amorphous solid dispersions of Naringenin with enhanced dissolution rate. Int J Pharm. 2020;583:119363.

  39. Han YR, Ma Y, Lee PI. Impact of phase separation morphology on release mechanism of amorphous solid dispersions. Eur J Pharm Sci. 2019;136:104955.

    Article  CAS  PubMed  Google Scholar 

  40. Shi NQ, Wang SR, Zhang Y, Huo JS, Wang LN, Cai JH, et al. Hot melt extrusion technology for improved dissolution, solubility and "spring-parachute" processes of amorphous self-micellizing solid dispersions containing BCS II drugs indomethacin and fenofibrate: Profiles and mechanisms. Eur J Pharm Sci. 2019;130:78–90.

    Article  CAS  PubMed  Google Scholar 

  41. Chen Y, Wang S, Wang S, Liu C, Su C, Hageman M, et al. Initial drug dissolution from amorphous solid dispersions controlled by polymer dissolution and drug-polymer interaction. Pharm Res. 2016;33(10):2445–58.

    Article  PubMed  Google Scholar 

  42. Liu C, Chen Z, Chen Y, Lu J, Li Y, Wang S, et al. Improving oral bioavailability of sorafenib by optimizing the “spring” and “parachute” based on molecular interaction mechanisms. Mol Pharm. 2016;13(2):599–608.

    Article  CAS  PubMed  Google Scholar 

  43. Arca HÇ, Mosquera-Giraldo LI, Dahal D, Taylor LS, Edgar KJJMP. Multidrug, anti-HIV amorphous solid dispersions: nature and mechanisms of impacts of drugs on each other’s solution concentrations. Mol Pharm. 2017;14(11):3617–27.

    Article  CAS  PubMed  Google Scholar 

  44. Graeser KA, Patterson JE, Zeitler JA, Rades TJP. The role of configurational entropy in amorphous systems. Pharmaceutics. 2010;2(2):224–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Craig DQJIjop. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm. 2002;231(2):131–44.

    Article  Google Scholar 

  46. Schittny A, Huwyler J, Puchkov M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. J Drug Deliv. 2020;27(1):110–27.

    Article  CAS  Google Scholar 

  47. Sun DD, Lee PI. Probing the mechanisms of drug release from amorphous solid dispersions in medium-soluble and medium-insoluble carriers. J Control Release. 2015;211:85–93.

    Article  CAS  PubMed  Google Scholar 

  48. Pandi P, Bulusu R, Kommineni N, Khan W, Singh M. Amorphous solid dispersions: an update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products. Int J Pharm. 2020;586:119560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Saboo S, Mugheirbi NA, Zemlyanov DY, Kestur US, Taylor LS. Congruent release of drug and polymer: A "sweet spot" in the dissolution of amorphous solid dispersions. J Control Release. 2019;298:68–82.

    Article  CAS  PubMed  Google Scholar 

  50. Li J, Li C, Zhang H, Gao X, Wang T, Wang Z, et al. Preparation of azithromycin amorphous solid dispersion by hot-melt extrusion: an advantageous technology with taste masking and solubilization effects. Polymers. 2022;14(3):495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Indulkar AS, Lou X, Zhang GG, Taylor LSJPR. Role of surfactants on release performance of amorphous solid dispersions of ritonavir and copovidone. Pharm Res. 2022;39(2):381–97.

    Article  CAS  PubMed  Google Scholar 

  52. Cho H-W, Baek S-H, Lee B-J, Jin H-EJP. Orodispersible polymer films with the poorly water-soluble drug, olanzapine: hot-melt pneumatic extrusion for single-process 3D printing. Pharmaceutics 2020;12(8):692.

  53. Tres F, Posada MM, Hall SD, Mohutsky MA, Taylor LSJIJoP. Mechanistic understanding of the phase behavior of supersaturated solutions of poorly water-soluble drugs. Int J Pharm. 2018;543(1–2):29–37.

    Article  CAS  PubMed  Google Scholar 

  54. Feng D, Peng T, Huang Z, Singh V, Shi Y, Wen T, et al. Polymer–surfactant system based amorphous solid dispersion: Precipitation inhibition and bioavailability enhancement of itraconazole. Pharmaceutics. 2018;10(2):53.

    Article  PubMed Central  Google Scholar 

  55. Kwon J, Giri BR, Song ES, Bae J, Lee J, Kim DWJP. Spray-dried amorphous solid dispersions of atorvastatin calcium for improved supersaturation and oral bioavailability. Pharmaceutics. 2019;11(9):461.

    Article  CAS  PubMed Central  Google Scholar 

  56. Lakshman D, Chegireddy M, Hanegave GK, Sree KN, Kumar N, Lewis SA, et al. Investigation of drug-polymer miscibility, biorelevant dissolution, and bioavailability improvement of Dolutegravir-polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer solid dispersions. Eur J pharm Sci. 2020;142:105137.

    Article  CAS  PubMed  Google Scholar 

  57. de Alencar Danda LJ, de Medeiros BL, Melo VCS, Sobrinho JLS, Soares MFdLRJEJoPS. Combining amorphous solid dispersions for improved kinetic solubility of posaconazole simultaneously released from soluble PVP/VA64 and an insoluble ammonio methacrylate copolymer. Eur J Pharm Sci. 2019;133:79–85.

    Article  Google Scholar 

  58. Figueirêdo CBM, Nadvorny D, de Medeiros Vieira ACQ, de Medeiros Schver GCR, Sobrinho JLS, Neto PJR, et al. Enhanced delivery of fixed-dose combination of synergistic antichagasic agents posaconazole-benznidazole based on amorphous solid dispersions. Eur J Pharm Sci. 2018;119:208–18.

    Article  PubMed  Google Scholar 

  59. Xi L, Song H, Wang Y, Gao H, Fu QJAP. Lacidipine amorphous solid dispersion based on hot melt extrusion: good miscibility, enhanced dissolution, and favorable stability. AAPS Pharm Sci Tech. 2018;19(7):3076–84.

    Article  CAS  Google Scholar 

  60. Gala U, Miller D, Williams ROJP. Improved dissolution and pharmacokinetics of abiraterone through KinetiSol® enabled amorphous solid dispersions. Pharmaceutics. 2020;12(4):357.

    Article  CAS  PubMed Central  Google Scholar 

  61. Monschke M, Kayser K, Wagner KGJAP. Influence of particle size and drug load on amorphous solid dispersions containing pH-dependent soluble polymers and the weak base ketoconazole. AAPS PharmSciTech. 2021;22(1):1–11.

    Article  Google Scholar 

  62. Umemoto Y, Uchida S, Yoshida T, Shimada K, Kojima H, Takagi A, et al. An effective polyvinyl alcohol for the solubilization of poorly water-soluble drugs in solid dispersion formulations. J Drug Deliv Sci Tech. 2020;55:101401.

    Article  CAS  Google Scholar 

  63. Pinto JMO, Leão AF, Alves GF, Mendes C, França MT, Fernandes D, et al. New supersaturating drug delivery system as strategy to improve apparent solubility of candesartan cilexetil in biorelevant medium. Pharm Develop. 2020;25(1):89–99.

    Article  CAS  Google Scholar 

  64. Shi X, Fan N, Zhang G, Sun J, He Z, Li JJPD, et al. Quercetin amorphous solid dispersions prepared by hot melt extrusion with enhanced solubility and intestinal absorption. J Pharm Develop Tech. 2020;25(4):472–81.

    Article  CAS  Google Scholar 

  65. Han F, Zhang W, Wang Y, Xi Z, Chen L, Li S, et al. Applying supercritical fluid technology to prepare ibuprofen solid dispersions with improved oral bioavailability. pharmaceutics. 2019;11(2):67.

  66. Alhayali A, Selo MA, Ehrhardt C, Velaga SJEJoPS. Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe. Eur J Pharm Sci. 2018;117:147–53.

    Article  CAS  PubMed  Google Scholar 

  67. Rahman M, Ahmad S, Tarabokija J, Parker N, Bilgili EJP. Spray-dried amorphous solid dispersions of griseofulvin in HPC/Soluplus/SDS: elucidating the multifaceted impact of sds as a minor component. Pharmaceutics. 2020;12(3):197.

    Article  CAS  PubMed Central  Google Scholar 

  68. Wang Z, Sun M, Liu T, Gao Z, Ye Q, Tan X, et al. Co-amorphous solid dispersion systems of lacidipine-spironolactone with improved dissolution rate and enhanced physical stability. Asian J Pharm Sci. 2019;14(1):95–103.

    Article  PubMed  Google Scholar 

  69. Himawan A, Djide NJN, Mardikasari SA, Utami RN, Arjuna A, Donnelly RF, et al. A novel in vitro approach to investigate the effect of food intake on release profile of valsartan in solid dispersion-floating gel in-situ delivery system. Eur J Pharm Sci. 2022;168:106057.

    Article  CAS  PubMed  Google Scholar 

  70. Müller M, Wiedey R, Hoheisel W, Serno P, Breitkreutz JJEJoP, Biopharmaceutics. Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions. Eur J Pharm Biopharm. 2021;169:189–199.

  71. Trasi NS, Bhujbal SV, Zemlyanov DY, Zhou QT, Taylor LSJIjopX. Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach. Int J Pharm. 2020;2:100052.

  72. Ren F, Sun H, Cui L, Si Y, Chen N, Ren G, et al. Antisolvent recrystallization strategy to screen appropriate carriers to stabilize filgotinib amorphous solid dispersions. J Pharm Sci. 2018;107(6):1624–32.

    Article  CAS  PubMed  Google Scholar 

  73. Dong W, Su X, Xu M, Hu M, Sun Y, Zhang PJAjops. Preparation, characterization, and in vitro/vivo evaluation of polymer-assisting formulation of atorvastatin calcium based on solid dispersion technique. Asian journal of pharmaceutical sciences. 2018;13(6):546–54.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Xie T, Taylor LSJJops. Effect of temperature and moisture on the physical stability of binary and ternary amorphous solid dispersions of celecoxib. J Pharm Sci. 2017;106(1):100–10.

    Article  CAS  PubMed  Google Scholar 

  75. Shi C, Tong Q, Fang J, Wang C, Wu J, Wang WJEJoPS. Preparation, characterization and in vivo studies of amorphous solid dispersion of berberine with hydrogenated phosphatidylcholine. Eur J Pharm Sci. 2015;74:11–7.

    Article  CAS  PubMed  Google Scholar 

  76. Rahman Z, Siddiqui A, Bykadi S, Khan MAJIJoP. Determination of tacrolimus crystalline fraction in the commercial immediate release amorphous solid dispersion products by a standardized X-ray powder diffraction method with chemometrics. Int J Pharm. 2014;475(1–2):462–70.

    Article  CAS  PubMed  Google Scholar 

  77. Nieto K, Mallery SR, Schwendeman SPJIjop. Microencapsulation of amorphous solid dispersions of fenretinide enhances drug solubility and release from PLGA in vitro and in vivo. Int J Pharm. 2020;586:119475.

  78. Ewing AV, Clarke GS, Kazarian SGJEJoPS. Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging. Eur J Pharm Sci. 2014;60:64–71.

    Article  CAS  PubMed  Google Scholar 

  79. Sarode AL, Malekar SA, Cote C, Worthen DRJCP. Hydroxypropyl cellulose stabilizes amorphous solid dispersions of the poorly water soluble drug felodipine. Carbohydrate Polymers. 2014;112:512–9.

    Article  CAS  PubMed  Google Scholar 

  80. Jijun F, Lishuang X, Xiaoguang T, Min S, Mingming Z, Haibing H, et al. The inhibition effect of high storage temperature on the recrystallization rate during dissolution of nimodipine-Kollidon VA64 solid dispersions (NM-SD) prepared by hot-melt extrusion. J Pharm Sci. 2011;100(5):1643–7.

    Article  PubMed  Google Scholar 

  81. Hassouna F, El Dahab MA, Fulem M, Haiek ADL, Laachachi A, Kopecký D, et al. Multi-scale analysis of amorphous solid dispersions prepared by freeze drying of ibuprofen loaded acrylic polymer nanoparticles. J Drug Deliv Sci. 2019;53:101182.

    Article  CAS  Google Scholar 

  82. Christina B, Taylor LS, Mauer LJJFRI. Physical stability of l-ascorbic acid amorphous solid dispersions in different polymers: a study of polymer crystallization inhibitor properties. Food Res Int. 2015;76:867–77.

    Article  CAS  PubMed  Google Scholar 

  83. Moes J, Koolen S, Huitema A, Schellens J, Beijnen J, Nuijen BJEjop, et al. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. Eur J Pharm Biopharm 2013;83(1):87–94.

  84. Thombre AG, Shah JC, Sagawa K, Caldwell WB. In vitro and in vivo characterization of amorphous, nanocrystalline, and crystalline ziprasidone formulations. Int J Pharm. 2012;428(1–2):8–17.

    Article  CAS  PubMed  Google Scholar 

  85. Kim YI, Kim KS, Suh KH, Shanmugam S, Woo JS, Yong CS, et al. New clopidogrel napadisilate salt and its solid dispersion with improved stability and bioequivalence to the commercial clopidogrel bisulphate salt in beagle dogs. Int J Pharm. 2011;415(1–2):129–39.

    Article  CAS  PubMed  Google Scholar 

  86. Lim HT, Balakrishnan P, Oh DH, Joe KH, Kim YR, Hwang DH, et al. Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: physicochemical characterization and pharmacokinetics in beagle dogs. Int J Pharm. 2010;397(1–2):225–30.

    Article  CAS  PubMed  Google Scholar 

  87. Yu DG, Yang JM, Branford-White C, Lu P, Zhang L, Zhu LM. Third generation solid dispersions of ferulic acid in electrospun composite nanofibers. Int J Pharm. 2010;400(1–2):158–64.

    Article  CAS  PubMed  Google Scholar 

  88. Mehanna MM, Motawaa AM, Samaha MW. In sight into tadalafil - block copolymer binary solid dispersion: Mechanistic investigation of dissolution enhancement. Int J Pharm. 2010;402(1–2):78–88.

    Article  CAS  PubMed  Google Scholar 

  89. Thiry J, Lebrun P, Vinassa C, Adam M, Netchacovitch L, Ziemons E, et al. Continuous production of itraconazole-based solid dispersions by hot melt extrusion: preformulation, optimization and design space determination. Int J Pharm. 2016;515(1–2):114–24.

    Article  CAS  PubMed  Google Scholar 

  90. Thiry J, Krier F, Ratwatte S, Thomassin J-M, Jerome C, Evrard BJEJoPS. Hot-melt extrusion as a continuous manufacturing process to form ternary cyclodextrin inclusion complexes. Eur. J Pharm Pharm Sci. 2017;96:590–7.

    CAS  Google Scholar 

  91. Maniruzzaman M, Morgan DJ, Mendham AP, Pang J, Snowden MJ, Douroumis DJIjop. Drug–polymer intermolecular interactions in hot-melt extruded solid dispersions. Int J Pharm. 2013;443(1–2):199–208.

    Article  CAS  PubMed  Google Scholar 

  92. LaFountaine JS, Jermain SV, Prasad LK, Brough C, Miller DA, Lubda D, et al. Enabling thermal processing of ritonavir-polyvinyl alcohol amorphous solid dispersions by KinetiSol(R) Dispersing. Eur J Pharm Biopharm. 2016;101:72–81.

    Article  CAS  PubMed  Google Scholar 

  93. Moseson DE, Taylor LS. The application of temperature-composition phase diagrams for hot melt extrusion processing of amorphous solid dispersions to prevent residual crystallinity. Int J Pharm. 2018;553(1–2):454–66.

    Article  CAS  PubMed  Google Scholar 

  94. Szabó E, Démuth B, Galata DL, Vass P, Hirsch E, Csontos I, et al. Continuous formulation approaches of amorphous solid dispersions: significance of powder flow properties and feeding performance. Pharmaceutics. 2019;11(12):654.

    Article  PubMed Central  Google Scholar 

  95. Muvva A, Lakshman D, Dwibhashyam VM, Dengale S, Lewis SAJJoDDS, Technology. In vitro-in silico evaluation of Apremilast solid dispersions prepared via Corotating Twin Screw Extruder. J Drug Deliv Sci Tech. 2020;59:101844.

  96. Manne ASN, Hegde AR, Raut SY, Rao RR, Kulkarni VI, Mutalik SJD, et al. Hot liquid extrusion assisted drug-cyclodextrin complexation: a novel continuous manufacturing method for solubility and bioavailability enhancement of drugs. J Drug Deliv. 2021;11(3):1273–87.

    CAS  Google Scholar 

  97. Solomon S, Iqbal J, Albadarin ABJEJoP, Biopharmaceutics. Insights into the ameliorating ability of mesoporous silica in modulating drug release in ternary amorphous solid dispersion prepared by hot melt extrusion. Eur J Pharm Biopharm. 2021;165:244–258.

  98. Emam MF, Taha NF, Emara LHJJoAPS. A novel combination of Soluplus® and Poloxamer for Meloxicam solid dispersions via hot melt extrusion for rapid onset of action—part 1: dissolution and stability studies. Journal of Applied Pharmaceutical. Science. 2021;11(02):141–50.

    CAS  Google Scholar 

  99. Giri BR, Kwon J, Vo AQ, Bhagurkar AM, Bandari S, Kim DWJP. Hot-melt extruded amorphous solid dispersion for solubility, stability, and bioavailability enhancement of telmisartan. Pharmaceuticals. 2021;14(1):73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Maniruzzaman M, Nair A, Scoutaris N, Bradley MS, Snowden M, Douroumis DJIjop. One-step continuous extrusion process for the manufacturing of solid dispersions. Int J Pharm. 2015;496(1):42–51.

    Article  CAS  PubMed  Google Scholar 

  101. Fu Q, Fang M, Hou Y, Yang W, Shao J, Guo M, et al. A physically stabilized amorphous solid dispersion of nisoldipine obtained by hot melt extrusion. Powder Technology. 2016;301:342–8.

    Article  CAS  Google Scholar 

  102. Turpin ER, Taresco V, Al-Hachami WA, Booth J, Treacher K, Tomasi S, et al. In silico screening for solid dispersions: the trouble with solubility parameters and chiFH. Mol Pharm. 2018;15(10):4654–67.

    Article  CAS  PubMed  Google Scholar 

  103. Tian Y, Jacobs E, Jones DS, McCoy CP, Wu H, Andrews GP. The design and development of high drug loading amorphous solid dispersion for hot-melt extrusion platform. Int J Pharm. 2020;586:119545.

    Article  CAS  PubMed  Google Scholar 

  104. Suryavanshi P, Banerjee S. Exploration of theoretical and practical evaluation on Kollidon®SR matrix mediated amorphous filament extrusion of norfloxacin by melt extrusion. Journal of Drug Delivery Science and Technology. 2022;67.

  105. Zhao Y, Inbar P, Chokshi HP, Malick AW, Choi DSJJops. Prediction of the thermal phase diagram of amorphous solid dispersions by Flory–Huggins theory. J Pharm Sci. 2011;100(8):3196–3207.

  106. Ha E-S, Choi DH, Baek I-h, Park H, Kim M-SJA. Enhanced oral bioavailability of resveratrol by using neutralized eudragit E solid dispersion prepared via spray drying. Antioxidants. 2021;10(1):90.

  107. Mudie DM, Buchanan S, Stewart AM, Smith A, Shepard KB, Biswas N, et al. A novel architecture for achieving high drug loading in amorphous spray dried dispersion tablets. Int J Pharm. 2020;2:100042.

    CAS  Google Scholar 

  108. Costa B, Sauceau M, Del Confetto S, Sescousse R, Ré M-IJEJoP, Biopharmaceutics. Determination of drug-polymer solubility from supersaturated spray-dried amorphous solid dispersions: a case study with Efavirenz and Soluplus®. Eur J Pharm Biopharm. 2019;142:300–306.

  109. Ziaee A, Albadarin AB, Padrela L, Faucher A, O'Reilly E, Walker GJEJoP, et al. Spray drying ternary amorphous solid dispersions of ibuprofen–an investigation into critical formulation and processing parameters. Eur J Pharm Biopharm. 2017;120:43–51.

  110. Beak I-H, Kim M-SJC, Bulletin P. Improved supersaturation and oral absorption of dutasteride by amorphous solid dispersions. Chemical. Pharmaceutical Bulletin. 2012;60(11):1468–73.

    Article  CAS  Google Scholar 

  111. Tran TH, Poudel BK, Marasini N, Chi S-C, Choi H-G, Yong CS, et al. Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray-drying technique without an organic solvent. Int J Pharm. 2013;443(1–2):50–7.

    Article  CAS  PubMed  Google Scholar 

  112. Metre S, Mukesh S, Samal SK, Chand M, Sangamwar ATJMp. Enhanced biopharmaceutical performance of rivaroxaban through polymeric amorphous solid dispersion. Mol Pharm. 2018;15(2):652–68.

    Article  CAS  PubMed  Google Scholar 

  113. Smeets A, Koekoekx R, Ruelens W, Smet M, Clasen C, Van den Mooter GJIJoP. Gastro-resistant encapsulation of amorphous solid dispersions containing darunavir by coaxial electrospraying. Int J Pharm. 2020;574:118885.

  114. Kawakami K, Miyazaki A, Fukushima M, Sato K, Yamamura Y, Mohri K, et al. Physicochemical properties of solid phospholipid particles as a drug delivery platform for improving oral absorption of poorly soluble drugs. Pharm Res. 2017;34(1):208–16.

    Article  CAS  PubMed  Google Scholar 

  115. Kawakami K, Zhang S, Chauhan RS, Ishizuka N, Yamamoto M, Masaoka Y, et al. Preparation of fenofibrate solid dispersion using electrospray deposition and improvement in oral absorption by instantaneous post-heating of the formulation. Int J Pharm. 2013;450(1–2):123–8.

    Article  CAS  PubMed  Google Scholar 

  116. Browne E, Charifou R, Worku ZA, Babu RP, Healy AMJIjop. Amorphous solid dispersions of ketoprofen and poly-vinyl polymers prepared via electrospraying and spray drying: a comparison of particle characteristics and performance. Int J Pharm. 2019;566:173–84.

    Article  CAS  PubMed  Google Scholar 

  117. Song S, Wang C, Wang S, Siegel RA, Sun CCJIJoP. Efficient development of sorafenib tablets with improved oral bioavailability enabled by coprecipitated amorphous solid dispersion. Int J Pharm. 2021;610:121216.

  118. Duarte Í, Corvo ML, Serôdio P, Vicente J, Pinto JF, Temtem MJEJoPS. Production of nano-solid dispersions using a novel solvent-controlled precipitation process—Benchmarking their in vivo performance with an amorphous micro-sized solid dispersion produced by spray drying. Eur J Pharm Sci. 2016;93:203–14.

    Article  CAS  PubMed  Google Scholar 

  119. Lim RTY, Ng WK, Tan RBJPt. Dissolution enhancement of indomethacin via amorphization using co-milling and supercritical co-precipitation processing. Powder Technology. 2013;240:79–87.

    Article  CAS  Google Scholar 

  120. Zhou H, Wang W, Hu H, Ni X, Ni S, Xu Y, et al. Co-precipitation of calcium carbonate and curcumin in an ethanol medium as a novel approach for curcumin dissolution enhancement. J Drug Deliv Sci Tech. 2019;51:397–402.

    Article  CAS  Google Scholar 

  121. Liu P, Zhou J-y, Chang J-h, Liu X-g, Xue H-f, Wang R-x, et al. Soluplus-mediated diosgenin amorphous solid dispersion with high solubility and high stability: development, characterization and oral bioavailability. Drug Design, Develop 2020;14:2959.

  122. Wang Y, Fang Y, Zhou F, Liang Q, Deng YJJoPS. The amorphous quercetin/hydroxypropylmethylcellulose acetate succinate solid dispersions prepared by co-precipitation method to enhance quercetin dissolution. J Pharm Sci. 2021;110(9):3230–7.

    Article  CAS  PubMed  Google Scholar 

  123. Islam MT, Scoutaris N, Maniruzzaman M, Moradiya HG, Halsey SA, Bradley MS, et al. Implementation of transmission NIR as a PAT tool for monitoring drug transformation during HME processing. Eur J Pharm Biopharm. 2015;96:106–16.

    Article  CAS  PubMed  Google Scholar 

  124. Saerens L, Vervaet C, Remon JP, De Beer T. Process monitoring and visualization solutions for hot-melt extrusion: a review. J Pharm Pharmacol. 2014;66(2):180–203.

    Article  CAS  PubMed  Google Scholar 

  125. Sacher S, Poms J, Rehrl J, Khinast JGJIjop. PAT implementation for advanced process control in solid dosage manufacturing–a practical guide. Int J Pharm. 2021;121408.

  126. Rehrl J, Karttunen AP, Nicolai N, Hormann T, Horn M, Korhonen O, et al. Control of three different continuous pharmaceutical manufacturing processes: Use of soft sensors. Int J Pharm. 2018;543(1–2):60–72.

    Article  CAS  PubMed  Google Scholar 

  127. Pauli V, Roggo Y, Pellegatti L, Nguyen Trung NQ, Elbaz F, Ensslin S, et al. Process analytical technology for continuous manufacturing tableting processing: a case study. J Pharm Biomed Anal. 2019;162:101–11. https://doi.org/10.1016/j.jpba.2018.09.016.

    Article  CAS  PubMed  Google Scholar 

  128. Esmonde-White KA, Cuellar M, Uerpmann C, Lenain B, Lewis IR. Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing. Anal Bioanal Chem. 2017;409(3):637–49. https://doi.org/10.1007/s00216-016-9824-1.

    Article  CAS  PubMed  Google Scholar 

  129. Schlindwein W, Bezerra M, Almeida J, Berghaus A, Owen M, Muirhead G. In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME). Pharmaceutics. 2018;10(4). https://doi.org/10.3390/pharmaceutics10040166.

  130. Yamanaka T, Kano S. Patent term extension systems differentiate Japanese and US drug lifecycle management. Drug Discov Today. 2016;21(1):111–7. https://doi.org/10.1016/j.drudis.2015.09.005.

    Article  PubMed  Google Scholar 

  131. Korasa K, Vrečer FJEJoPS. Overview of PAT process analysers applicable in monitoring of film coating unit operations for manufacturing of solid oral dosage forms. Eur J Pharm Sci. 2018;111:278–92.

    Article  CAS  PubMed  Google Scholar 

  132. Harting J, Kleinebudde PJEJoP, Biopharmaceutics. Optimisation of an in-line Raman spectroscopic method for continuous API quantification during twin-screw wet granulation and its application for process characterisation. Eur J Pharm Biopharm. 2019;137:77–85.

    Article  CAS  PubMed  Google Scholar 

  133. Vargas JM, Nielsen S, Cárdenas V, Gonzalez A, Aymat EY, Almodovar E, et al. Process analytical technology in continuous manufacturing of a commercial pharmaceutical product. Int J Pharm. 2018;538(1–2):167–78.

    Article  CAS  PubMed  Google Scholar 

  134. Chablani L, Taylor MK, Mehrotra A, Rameas P, Stagner WCJAP. Inline real-time near-infrared granule moisture measurements of a continuous granulation–drying–milling process. AAPS PharmSciTech. 2011;12(4):1050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Silva BS, Colbert M-J, Santangelo M, Bartlett JA, Lapointe-Garant P-P, Simard J-S, et al. Monitoring microsphere coating processes using PAT tools in a bench scale fluid bed. Eur J Pharm Sci. 2019;135:12–21.

    Article  Google Scholar 

  136. Domokos A, Pusztai É, Madarász L, Nagy B, Gyürkés M, Farkas A, et al. Combination of PAT and mechanistic modeling tools in a fully continuous powder to granule line: rapid and deep process understanding. Powder Technology. 2021;388:70–81.

    Article  CAS  Google Scholar 

  137. Krier F, Mantanus J, Sacre PY, Chavez PF, Thiry J, Pestieau A, et al. PAT tools for the control of co-extrusion implants manufacturing process. Int J Pharm. 2013;458(1):15–24.

    Article  CAS  PubMed  Google Scholar 

  138. Galata DL, Meszaros LA, Ficzere M, Vass P, Nagy B, Szabo E, et al. Continuous blending monitored and feedback controlled by machine vision-based PAT tool. J Pharm Biomed Anal. 2021;196:113902.

    Article  CAS  PubMed  Google Scholar 

  139. Meszaros LA, Galata DL, Madarasz L, Kote A, Csorba K, David AZ, et al. Digital UV/VIS imaging: a rapid PAT tool for crushing strength, drug content and particle size distribution determination in tablets. Int J Pharm. 2020;578:119174.

    Article  CAS  PubMed  Google Scholar 

  140. Guay JM, Lapointe-Garant PP, Gosselin R, Simard JS, Abatzoglou N. Development of a multivariate light-induced fluorescence (LIF) PAT tool for in-line quantitative analysis of pharmaceutical granules in a V-blender. Eur J Pharm Biopharm. 2014;86(3):524–31.

    Article  CAS  PubMed  Google Scholar 

  141. Ponnammal P, Kanaujia P, Yani Y, Ng WK, Tan RBJP. Orally disintegrating tablets containing melt extruded amorphous solid dispersion of tacrolimus for dissolution enhancement. Pharmaceutics. 2018;10(1):35.

    Article  PubMed Central  Google Scholar 

  142. Anane-Adjei AB, Jacobs E, Nash SC, Askin S, Soundararajan R, Kyobula M, et al. Amorphous solid dispersions: Utilization and challenges in preclinical drug development within AstraZeneca. Int J Pharm. 2022;614:121387.

    Article  CAS  PubMed  Google Scholar 

  143. Adelusi TI, Oyedele A-QK, Boyenle ID, Ogunlana AT, Adeyemi RO, Ukachi CD, et al. Molecular modeling in drug discovery. Informatics in Medicine Unlocked. 2022;100880.

  144. Glaab EJBiB. Building a virtual ligand screening pipeline using free software: a survey. Briefings in Bioinformatics. 2016;17(2):352–66.

    Article  Google Scholar 

  145. Silver M, Cohen L. Monte Carlo simulation of anomalous transit-time dispersion of amorphous solids. Physical Review B. 1977;15(6):3276–8.

    Article  CAS  Google Scholar 

  146. Eckert M, Neyts E, Bogaerts A. Modeling adatom surface processes during crystal growth: a new implementation of the Metropolis Monte Carlo algorithm. CrystEngComm. 2009;11(8).

  147. Schlick T. Molecular modeling and simulation: an interdisciplinary guide: Springer; 2010.

    Book  Google Scholar 

  148. McCammon JA, Gelin BR. Karplus MJn. Dynamics of folded proteins. Natures. 1977;267(5612):585–90.

    CAS  Google Scholar 

  149. Cui YJJoPS. Using molecular simulations to probe pharmaceutical materials. J Pharm Sci. 2011;100(6):2000–19.

    Article  Google Scholar 

  150. Vogiatzis GG, Theodorou DNJAoCMiE. Multiscale molecular simulations of polymer-matrix nanocomposites. Archives of Computational Methods in Engineering. 2018;25(3):591–645.

    Article  PubMed  Google Scholar 

  151. Ojo AT, Lee PIJJoPS. A mechanistic model for predicting the physical stability of amorphous solid dispersions. J Pharm Sci. 2021;110(4):1495–512.

    Article  CAS  PubMed  Google Scholar 

  152. Huynh L, Grant J, Leroux J-C, Delmas P, Allen CJPr. Predicting the solubility of the anti-cancer agent docetaxel in small molecule excipients using computational methods. Pharm Res. 2008;25(1):147–57.

    Article  CAS  PubMed  Google Scholar 

  153. Giulini M, Rigoli M, Mattiotti G, Menichetti R, Tarenzi T, Fiorentini R, et al. From system modeling to system analysis: The impact of resolution level and resolution distribution in the computer-aided investigation of biomolecules. Frontiers in Molecular Biosciences. 2021;8.

  154. Wegiel LA, Mauer LJ, Edgar KJ, Taylor LSJJops. Crystallization of amorphous solid dispersions of resveratrol during preparation and storage—Impact of different polymers. J Pharm Sci. 2013;102(1):171–84.

    Article  CAS  PubMed  Google Scholar 

  155. Yang F, Su Y, Small J, Huang C, Martin GE, Farrington AM, et al. Probing the molecular-level interactions in an active pharmaceutical ingredient (API)-polymer dispersion and the resulting impact on drug product formulation. Pharm Res. 2020;37(6):1–16.

    Article  CAS  Google Scholar 

  156. Telang C, Mujumdar S, Mathew MJJops. Improved physical stability of amorphous state through acid base interactions. J Pharm Sci. 2009;98(6):2149–59.

    Article  CAS  PubMed  Google Scholar 

  157. Barmpalexis P, Karagianni A, Katopodis K, Vardaka E, Kachrimanis KJEJoPS. Molecular modelling and simulation of fusion-based amorphous drug dispersions in polymer/plasticizer blends. Eur J Pharm Sci. 2019;130:260–8.

    Article  CAS  PubMed  Google Scholar 

  158. Fule R, Meer T, Sav A, Amin PJJopi. Solubility and dissolution rate enhancement of lumefantrine using hot melt extrusion technology with physicochemical characterisation. Journal of pharmaceutical investigation. 2013;43(4):305–21.

    Article  CAS  Google Scholar 

  159. Gangurde AB, Kundaikar HS, Javeer SD, Jaiswar DR, Degani MS, Amin PDJJoDDS, et al. Enhanced solubility and dissolution of curcumin by a hydrophilic polymer solid dispersion and its insilico molecular modeling studies. J Drug Deliv Sci Tech 2015;29:226–237.

  160. Macháčková M, Tokarský J, Čapková PJEJoPS. A simple molecular modeling method for the characterization of polymeric drug carriers. Eur J Pharm Sci. 2013;48(1–2):316–22.

    Article  PubMed  Google Scholar 

  161. Ma S-M, Zhao L, Wang Y-L, Zhu Y-L, Lu Z-YJPCCP. The coarse-grained models of poly (ethylene oxide) and poly (propylene oxide) homopolymers and poloxamers in big multipole water (BMW) and MARTINI frameworks. Phys Chem Chem Phys. 2020;22(28):15976–85.

    Article  CAS  PubMed  Google Scholar 

  162. Rigby D, Sun H, Eichinger BJPI. Computer simulations of poly (ethylene oxide): force field, pvt diagram and cyclization behaviour. Polymer Int. 1997;44(3):311–30.

    Article  CAS  Google Scholar 

  163. Sun HJTJoPCB. COMPASS: an ab initio force-field optimized for condensed-phase applications overview with details on alkane and benzene compounds. J Phy Chem. 1998;102(38):7338–64.

    Article  Google Scholar 

  164. Wang J, Wang W, Kollman PA. Case DAJJomg, modelling. Automatic atom type and bond type perception in molecular mechanical calculations. J Mol Graphics. 2006;25(2):247–60.

    Article  Google Scholar 

  165. Jorgensen WL, Maxwell DS, Tirado-Rives JJJotACS. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. Journal of the American Chemical Society 1996;118(45):11225–11236.

  166. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Sa S, Karplus MJJocc. CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. Journal of computational chemistry. 1983;4(2):187–217.

    Article  CAS  Google Scholar 

  167. MacKerell AD Jr, Banavali N, Foloppe NJBORoB. Development and current status of the CHARMM force field for nucleic acids. Biopolymers. 2000;56(4):257–65.

    Article  CAS  PubMed  Google Scholar 

  168. Bhattacharya S, Suryanarayanan RJJops. Local mobility in amorphous pharmaceuticals—characterization and implications on stability. J Pharm Sci. 2009;98(9):2935–53.

    Article  CAS  PubMed  Google Scholar 

  169. Kothari K, Ragoonanan V, Suryanarayanan RJMp. Influence of molecular mobility on the physical stability of amorphous pharmaceuticals in the supercooled and glassy states. Mol Pharm. 2014;11(9):3048–55.

    Article  CAS  PubMed  Google Scholar 

  170. Gupta J, Nunes C, Vyas S, Jonnalagadda SJTJoPCB. Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations. J Phys Chem. 2011;115(9):2014–23.

    Article  CAS  Google Scholar 

  171. Kapourani A, Chatzitheodoridou M, Kontogiannopoulos KN, Barmpalexis PJMP. Experimental, thermodynamic, and molecular modeling evaluation of amorphous simvastatin-poly (vinylpyrrolidone) solid dispersions. Mol Pharm. 2020;17(7):2703–20.

    Article  CAS  PubMed  Google Scholar 

  172. Yani Y, Kanaujia P, Chow PS, Tan RBJI, Research EC. Effect of API-Polymer miscibility and interaction on the stabilization of amorphous solid dispersion: a molecular simulation study. Ind Eng Chem Res. 2017;56(44):12698–707.

    Article  Google Scholar 

  173. Han R, Huang T, Liu X, Yin X, Li H, Lu J, et al. Insight into the dissolution molecular mechanism of ternary solid dispersions by combined experiments and molecular simulations. AAPS PharmSciTech. 2019;20(7):1–14.

    Article  Google Scholar 

  174. Razmimanesh F, Amjad-Iranagh S, Modarress HJJoMM. Molecular dynamics simulation study of chitosan and gemcitabine as a drug delivery system. J Mol Model. 2015;21(7):1–14.

    Article  CAS  Google Scholar 

  175. Xiang T-X, Anderson BDJJops. Molecular dynamics simulation of amorphous hydroxypropylmethylcellulose and its mixtures with felodipine and water. J Pharm Sci. 2017;106(3):803–16.

    Article  CAS  PubMed  Google Scholar 

  176. Mazurek AH, Szeleszczuk Ł, Pisklak DMJP. Periodic DFT calculations—review of applications in the pharmaceutical sciences. Pharmaceutics. 2020;12(5):415.

    Article  CAS  PubMed Central  Google Scholar 

  177. Meng F, Trivino A, Prasad D, Chauhan HJEJoPS. Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. Eur J Pharm Sci. 2015;71:12–24.

    Article  CAS  PubMed  Google Scholar 

  178. Maniruzzaman M, Pang J, Morgan DJ, Douroumis DJMp. Molecular modeling as a predictive tool for the development of solid dispersions. Mol Pharm. 2015;12(4):1040–9.

    Article  CAS  PubMed  Google Scholar 

  179. Nie H, Mo H, Zhang M, Song Y, Fang K, Taylor LS, et al. Investigating the interaction pattern and structural elements of a drug–polymer complex at the molecular level. Mol Pharm. 2015;12(7):2459–68.

    Article  CAS  PubMed  Google Scholar 

  180. Wang B, Wang D, Zhao S, Huang X, Zhang J, Lv Y, et al. Evaluate the ability of PVP to inhibit crystallization of amorphous solid dispersions by density functional theory and experimental verify. Eur J Pharm Sci. 2017;96:45–52.

    Article  CAS  PubMed  Google Scholar 

  181. Elbadawi M, Gaisford S, Basit AW. Advanced machine-learning techniques in drug discovery. J Drug Deliv Sci Tech. 2021;26(3):769–77.

    CAS  Google Scholar 

  182. Mehta CH, Narayan R, Nayak UYJDDT. Computational modeling for formulation design. Drug Discovery Today. 2019;24(3):781–8.

    Article  CAS  PubMed  Google Scholar 

  183. Rantanen J, Khinast JJJops. The future of pharmaceutical manufacturing sciences. J Pharm Sci. 2015;104(11):3612–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Yoshida F, Topliss JGJJomc. QSAR model for drug human oral bioavailability. J Medi Chem. 2000;43(13):2575–85.

    Article  CAS  Google Scholar 

  185. Huang Y, Dai W-GJAPSB. Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharmaceutica Sinica B. 2014;4(1):18–25.

    Article  PubMed  Google Scholar 

  186. Ricarte RG, Van Zee NJ, Li Z, Johnson LM, Lodge TP, Hillmyer MAJMp. Recent advances in understanding the micro-and nanoscale phenomena of amorphous solid dispersions. Mol Pharm. 2019;16(10):4089–103.

    Article  CAS  PubMed  Google Scholar 

  187. Chan T. Ouyang DJajops. Investigating the molecular dissolution process of binary solid dispersions by molecular dynamics simulations. asian journal of pharmaceutical sciences. 2018;13(3):248–54.

    PubMed  Google Scholar 

  188. Jha PK, Larson RGJMp. Assessing the efficiency of polymeric excipients by atomistic molecular dynamics simulations. Mol Pharm. 2014;11(5):1676–86.

    Article  CAS  PubMed  Google Scholar 

  189. LaFountaine JS, McGinity JW, Williams ROJAP. Challenges and strategies in thermal processing of amorphous solid dispersions: a review. AAPS Pharmscitech. 2016;17(1):43–55.

    Article  CAS  PubMed  Google Scholar 

  190. AboulFotouh K, Zhang Y, Maniruzzaman M, Williams III RO, Cui ZJIJoP. Amorphous solid dispersion dry powder for pulmonary drug delivery: Advantages and challenges. Int J Pharm. 2020;587:119711.

  191. Mangal S, Park H, Zeng L, Heidi HY, Lin Y-w, Velkov T, et al. Composite particle formulations of colistin and meropenem with improved in-vitro bacterial killing and aerosolization for inhalation. Int J Pharm. 2018;548(1):443–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Pawar J, Tayade A, Gangurde A, Moravkar K, Amin P. Solubility and dissolution enhancement of efavirenz hot melt extruded amorphous solid dispersions using combination of polymeric blends: a QbD approach. Eur J Pharm Sci. 2016;88:37–49. https://doi.org/10.1016/j.ejps.2016.04.001.

    Article  CAS  PubMed  Google Scholar 

  193. Rathod V, Stagner WC, Gajera B, Haware RV. Hybridized nanoamorphous micellar dispersion using a QbD-DM(3) linked rational product design strategy for ritonavir: A BCS IV drug. Int J Pharm. 2020;588:119727. https://doi.org/10.1016/j.ijpharm.2020.119727.

    Article  CAS  PubMed  Google Scholar 

  194. Jana S, Ali SA, Nayak AK, Sen KK, Basu SKJCER, Design. Development of topical gel containing aceclofenac-crospovidone solid dispersion by “quality by design (QbD)” approach. Chemical Engineering Research. 2014;92(11):2095–105.

    Article  CAS  Google Scholar 

  195. Kaur P, Singh SK, Garg V, Gulati M, Vaidya YJPT. Optimization of spray drying process for formulation of solid dispersion containing polypeptide-k powder through quality by design approach. Powder Technology. 2015;284:1–11.

    Article  CAS  Google Scholar 

  196. Pawar J, Suryawanshi D, Moravkar K, Aware R, Shetty V, Maniruzzaman M, et al. Study the influence of formulation process parameters on solubility and dissolution enhancement of efavirenz solid solutions prepared by hot-melt extrusion: a QbD methodology. Drug Delivery Translational Research. 2018;8(6):1644–57.

    Article  CAS  PubMed  Google Scholar 

  197. Chavan RB, Thipparaboina R, Yadav B, Shastri NRJD. research t. Continuous manufacturing of co-crystals: challenges and prospects. Drug delivery translational research. 2018;8(6):1726–39.

    Article  CAS  PubMed  Google Scholar 

  198. Thakral NK, Mohapatra S, Stephenson GA, Suryanarayanan R. Compression-induced crystallization of amorphous indomethacin in tablets: characterization of spatial heterogeneity by two-dimensional X-ray diffractometry. Mol Pharm. 2015;12(1):253–63.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the Indian Institute of Technology (Banaras Hindu University), Varanasi, for providing infrastructure facilities. AM Healy acknowledges funding from Science Foundation Ireland under grant number 12/RC/2275_P2 co-funded under the European Regional Development Fund.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, 221005, India

    Amritha G Nambiar, Maan Singh, Abhishek R Mali, Rajnish Kumar, Ashish Kumar Agrawal & Dinesh Kumar

  2. School of Pharmacy, Complutense University, Madrid, Spain

    Dolores R Serrano

  3. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland

    Anne Marie Healy

Authors
  1. Amritha G Nambiar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maan Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abhishek R Mali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dolores R Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rajnish Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anne Marie Healy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ashish Kumar Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dinesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Amritha G. Nambiar: conceptualization, literature survey, a compilation of data, and original draft writing. Maan Singh: writing, reviewing, and editing. Abhishek R Mali: writing, review, and editing. Dolores R. Serano: writing, editing, and reviewing. Rajnish Kumar: writing, editing, and reviewing. Anne Marie Healy: conceptualization, writing, editing, and reviewing. Ashish Kumar Agrawal: writing, editing, and reviewing. Dinesh Kumar: conceptualization, writing, editing, reviewing, overall modification, and correction. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Dinesh Kumar.

Ethics declarations

Ethics Approval

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nambiar, A.G., Singh, M., Mali, A.R. et al. Continuous Manufacturing and Molecular Modeling of Pharmaceutical Amorphous Solid Dispersions. AAPS PharmSciTech 23, 249 (2022). https://doi.org/10.1208/s12249-022-02408-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-022-02408-4

Keywords

Search

Navigation