A systematic and robust assessment of hot-melt extrusion-based amorphous solid dispersions: Theoretical prediction to practical implementation

https://doi.org/10.1016/j.ijpharm.2022.121951Get rights and content

Abstract

Amorphous solid dispersions (ASDs) have gained attention as a formulation strategy in recent years, with the potential to improve the apparent solubility and, hence, the oral bioavailability of poorly soluble drugs. The process of formulating ASDs is commonly faced with challenges owing to the intrinsic physical and chemical instability of the initial amorphous form and the long-term physical stability of drug formulations. Numerous research publications on hot-melt extrusion (HME) technology have demonstrated that it is the most efficient approach for manufacturing reasonably stable ASDs. The HME technique has been established as a faster scale-up production strategy for formulation evaluation and has the potential to minimize the time to market. Thermodynamic evaluation and theoretical predictions of drug-polymer solubility and miscibility may assist to reduce the product development cost by HME. This review article highlights robust and established prediction theories and experimental approaches for the selection of polymeric carriers for the development of hot melt extrusion based stable amorphous solid dispersions (ASDs). In addition, this review makes a significant contribution to the literature as a pilot guide for ASD assessment, as well as to confirm the drug-polymer compatibility and physical stability of HME-based formulations.

Introduction

In the pharmaceutical manufacturing industry, oral ingestion is the most favored mode of administration among other drug delivery routes. The preferred delivery route is the oral one owing to the ease of drug administration, patient compliance, economic gain, lack of sterility restrictions, and versatility in dosage form design. However, some drugs have local effects in the gut, while the majority are delivered to the bloodstream through the systemic circulation and function in other areas of the body (Homayun et al., 2019). The production of new active pharmaceutical ingredients (APIs) faces a significant challenge in the development of oral pharmaceutical products owing to their poor solubility and dissolution behavior (Savjani et al., 2012). The major concern with poorly soluble drugs is that the therapeutic dosage of the API will not dissolve in the required volume of gastrointestinal fluids. The Biopharmaceutical Classification System (BCS) uses mathematical analysis to assess drug solubility and permeability in experimental settings (Saxena and Jain, 2019).

Pharmaceutical formulation researchers are keen on developing safe, practical, cost-effective, and scalable methods for drugs with low solubility and permeability based on the BCS. Amorphous solid dispersions (ASDs) molecularly dissolve poorly soluble APIs in a suitable polymer carrier, convert them into an amorphous state, and are considered a promising strategy for overcoming the aqueous solubility limitation and kinetic absorption issues. Based on the BCS classification, drugs can be classified into four classes based on their solubility and permeability properties: class I (high solubility and high permeability), class II (low solubility and high permeability), class III (high solubility and low permeability), and class IV (low solubility and low permeability) (Papich and Martinez, 2015). The ASD approach is an ideal technology for preparing successful forms of BCS class II/IV APIs. The solubility of an API substance is improved by disarranging its crystalline lattice to achieve a higher-energy amorphous state in ASDs (Duarte et al., 2015). The principal advantage of ASDs is that the API is in a high-energy state, enabling gut supersaturation and an increase in the absorption rate as the apparent solubility increases.

In recent decades, hot-melt extrusion (HME) technology as thermal processing has attracted a great deal of attention from the pharmaceutical industry as a promising solvent-free continuous process with a wide range of applications in drug development. The continuous processing and versatility to provide improved process control and promote the scalability of this technology mean that it can be used for expanded pharmaceutical development alongside other emerging technologies (such as 3D printing) and applications (Fig. 1). Several HME commercial products approved by the Food and Drug Administration (FDA), currently available in the market with different release targets, prove the potential and success of this technology (Table 1) (Tiwari et al., 2016, Alshehri et al., 2020).

The primary objective of using HME is to enhance the solubility and permeability and to improve the bioavailability (BA) of poorly soluble drugs, mainly through ASDs, to achieve optimum therapeutic efficacy (Ashour et al., 2016, Alshehri et al., 2019). The wide range of the applicability of HME in different pharmaceutical drug delivery systems makes it a robust technology. A variety of common drug delivery approaches and applications of the HME technique have been reported (Fig. 2) (Simões et al., 2019).

The range of HME applications includes solubility/bioavailability enhancement (Ashour et al., 2016), nanotechnology, nanostructured lipids (Bhagurkar et al., 2017), solid lipid nanoparticles (Bagde et al., 2019), transdermal applications (Marreto et al., 2020, Mendonsa et al., 2018), taste masking (Malaquias et al., 2018, Wang et al., 2020), enteric formulations (Alsulays et al., 2017), abuse-deterrent/tamper resistance (Butreddy et al., 2020, Baronsky-Probst et al., 2016), controlled (Alqahtani et al., 2020), extended, and sustained release delivery systems (Sawant et al., 2018), targeted drug delivery systems (Bruce et al., 2005), orodispersible forms (Pimparade et al., 2017), and floating formulations (Vo et al., 2016). Owing to its scalability and solvent-free process, HME technology in recent years has been adopted in the melt extrusion of amorphous drugs (Kallakunta et al., 2020, Tian et al., 2020), the synthesis of co-crystals (Srinivasan et al., 2020, Narala et al., 2020), chronotherapeutic systems (Dumpa et al., 2018), 3D printing (Zhang et al., 2017, Tan et al., 2018), foam extrusion (Almutairi et al., 2019), nanocrystal solid dispersions (Ye et al., 2016), and reactive extrusion (Haser et al., 2016).

Despite these advantages, the main drawback of this ASD approach is that it lacks the requisite stability and can revert to the crystalline form when stored. The physical and chemical properties of this system can change drastically at critical temperatures (Tg) and higher relative humidity, rendering it thermodynamically unstable and prone to crystallization. Significant upfront developments are required to produce stable amorphous formulations. The choice of polymer and quantity cannot be predicted with absolute certainty; and some general theories can be used to accelerate the formulation choice process. The pre-formulation study for the formulation composition materials and their compatibility is a key factor for the HME to achieve a robust process and good quality of the output product. Thermodynamic evaluation and the theoretical prediction of the drug-polymer solubility and miscibility can reduce the material cost and the time of product development by using the HME technology (Maniruzzaman et al., 2012). Understanding and predicting drug-carrier miscibility is a critical step in the HME process to maintain the physical stability of the drug to the carrier's molecular mobility. The immiscibility of the formulation components dominates the crystallization behavior of the mixture, which can lead to minimal physical stability (Hanada et al., 2018). Achieving extrudable and stable products requires a carrier (polymers or lipids) that exhibits thermoplastic characteristics with a desirable range limit of the extrusion temperature. The characteristic method for selecting a suitable polymeric carrier is a crucial step in the formulation process for developing a stable ASD of high quality. An ideal carrier should be able to perform multiple tasks, such as boosting the solubility and dissolving the API in the formulation. Various approaches can accomplish this, including particle size reduction, enhanced wettability, and the drug's amorphous form. Furthermore, the carrier should provide physical stability for the fabrication of dispersion particularly important if drug is in amorphous form (Nair et al., 2020).The industry's attention on the production of novel polymers used in pharmaceutical applications has gradually increased over the last two decades. Commonly used polymers for HME applications and pharmaceutical products are listed in Table 2, according to previous research (Siepmann et al., 2019).

This review appraises the robust pathway using available prediction theories and experimental techniques reported in the literature for the production of stable HME formulations. The evaluation of the chemical and physical properties of the fundamental material for the ASD system consists mainly of two stages (theoretical and experimental) during the process of polymeric carrier selection (Fig. 3) (Marsac et al., 2008, Zhao et al., 2011).

First, theoretical predictions of the thermodynamic assessment and solubility compatibility were made using the Gordon-Taylor equation, Hansen solubility parameters, Flory–Huggins interaction parameter, phase diagrams, Arrhenius equation, Kohlrausch–Williams–Watts equation, and Adam–Gibbs equation. These are considered to be the comprehensive thermal characterization theories discussed in this review and can be useful mathematical prediction tools for fundamental material descriptors that will eventually lead to ASD formulations with more stable products. Second, lab-based evaluations using various analytical methods were employed to confirm the compatibility of API with suitable miscibility and other chemical properties. The various analytical techniques (Table 3) have been used for the thermal characterization of the components of the HME system (Marsac et al., 2006).

Section snippets

Drug-polymer solubility/miscibility analysis

ASDs are among the most widely accepted formulation approaches to improve the solubility and bioavailability of poorly soluble active substances. However, the major drawback of ASDs is that they lack the necessary stability, and the amorphous drug reverts to its highly stable crystalline form during storage. Drug recrystallization within ASDs affects the stability of the formulation, resulting in reduced solubility and bioavailability. Various kinetic factors that affect the stability of the

Drug-polymer miscibility and solubility of the drug in polymers

Drug-polymer miscibility and solubility in polymers play vital roles in the development of a stable amorphous dispersion. Within ASDs, the drug must be distributed uniformly within the polymeric matrix. An immiscible system of drugs and polymers results in a non-homogeneous distribution of formulation components, resulting in the existence of drug-rich and polymer-rich domains. The miscibility of drugs and polymers must be determined in the early stages of development during polymer screening.

Residual drug crystals

The prepared ASDs should be free of crystalline drug particles. Even the existence of drug crystals at the nanoscale level can induce the recrystallization of the drug, thereby affecting the stability of the formulation. Advanced characterization techniques with high resolution must be adapted to screen small crystalline domains within the formulations (Shah et al., 2006).

Molecular mobility

Temperature and humidity are two significant factors that act as driving forces for enhanced molecular mobility. The storage of formulations at a temperature greater than the Tg of amorphous dispersion and uptake of moisture results in molecular mobility-induced phase separation and recrystallization of the drug (Hancock et al., 1995). Rapid screening techniques such as dynamic vapor sorption (DVS) provide the opportunity to expose amorphous dispersions to high humidity conditions by

Physical stability of the amorphous drug

The stability of amorphous drugs also affects the stability of ASDs. Higher stability in the amorphous drug results in enhanced stability in the corresponding dispersion. Various studies have reported improved stability of amorphous dispersions, where the drug alone has good stability in its amorphous state without recrystallization (Kapourani et al., 2021, Kapourani et al., 2021, Bhujbal et al., 2021).

Drug-polymer interactions

Interactions between drugs and polymers constitute an alternative approach to enhance the stability of ASDs. The molecular interactions formed between the drug and the polymer reduce the mobility of the drug, thus preventing recrystallization and phase separation. Most of the interactions involved are hydrogen bonding or acid-base reactions. H-bonding mainly occurs with components containing carboxyl, amine, and hydroxyl groups (Li et al., 2017, Beneš et al., 2017).

H-bonding may not preserve

Manufacturing process

The stability of the ASDs also depends on the manufacturing process employed to develop the formulation. Various manufacturing techniques, such as solvent evaporation for ASD production, depend primarily on standard solvency potential and flash solvent evaporation and can be easily adapted to spray drying (also based on the solvent evaporation principle) (Chavan et al., 2020). Spray drying is a well-defined technique in the manufacture of pharmaceutical products. It is employed in various

Environmental factors

The storage temperature and humidity play an essential role in preserving the stability of the formulation throughout its shelf life. The Tg value of ASD plays a vital role in determining the stability of the formulation. ASDs must be stored at temperatures below the Tg of the dispersion. At a temperature close to the dispersion Tg, the polymer exists as a soft rubbery material that promotes the mobility of amorphous drugs, resulting in the formation of drug-rich and polymer-rich domains, which

Thermal conductivity prediction models

The ultimate aim of an amorphous system is to develop a miscible binary system with a suitable API and carriers to provide a thermodynamically stable atmosphere. The selection of polymers (carriers) should rely on various aspects that should be considered for the solubility, miscibility, chemical and physical stability of the HME outcome products with regard to the proposed models (Haser and Zhang, 2018).

Conclusions and future outlook

The vast number of HME-related published papers and the increasing number of HME products in the pharmaceutical market demonstrate the applicability and promising nature of ASD formulations as a strategy to enhance the dissolution behavior and apparent solubility of poorly soluble drugs. Selecting compatible and miscible polymeric carriers for ASD formulations is crucial to guarantee formulation performance and stability during the shelf life of the final product. Different analytical lab

Funding

This project was also partially supported by Grant Number P30GM122733 funded by the National Institute of General Medical Sciences (NIGMS) a component of the National Institutes of Health (NIH) as one of its Centers of Biomedical Research Excellence (COBRE).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (221)

  • L.D. Bruce et al.

    Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid

    Eur. J. Pharm. Biopharm.

    (2005)
  • A. Butreddy et al.

    Extended release pellets prepared by hot melt extrusion technique for abuse deterrent potential: Category-1 in-vitro evaluation

    Int. J. Pharm.

    (2020)
  • K. Chmiel et al.

    Broadband dielectric spectroscopy as an experimental alternative to calorimetric determination of the solubility of drugs into polymer matrix: Case of flutamide and various polymeric matrixes

    Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahrenstechnik EV

    (2019)
  • K.J. Crowley et al.

    The use of thermal methods for predicting glass-former fragility. Thermochim

    Acta, New Adv. Pharm. Therm. Analy.

    (2001)
  • R.L. Danley

    New heat flux DSC measurement technique

    Thermochim. Acta

    (2002)
  • K. DeBoyace et al.

    The Application of Modeling and Prediction to the Formation and Stability of Amorphous Solid Dispersions

    J. Pharm. Sci.

    (2018)
  • D. Engers et al.

    A Solid-State Approach to Enable Early Development Compounds: Selection and Animsal Bioavailability Studies of an Itraconazole Amorphous Solid Dispersion

    J. Pharm. Sci.

    (2010)
  • W. Fan et al.

    The Preparation of Curcumin Sustained-Release Solid Dispersion by Hot Melt Extrusion—Ⅰ. Optimization of the Formulation

    J. Pharm. Sci.

    (2020)
  • A. Forster et al.

    Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis

    Int. J. Pharm.

    (2001)
  • A. Gryczke et al.

    Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion

    Colloids Surf. B Biointerfaces

    (2011)
  • K. Grzybowska et al.

    Recent developments in the experimental investigations of relaxations in pharmaceuticals by dielectric techniques at ambient and elevated pressure

    Adv. Drug Deliv. Rev., Amorphous Pharm. Solids

    (2016)
  • Y. Guo et al.

    Physical stability of pharmaceutical formulations: solid-state characterization of amorphous dispersions

    TrAC Trends Anal. Chem.

    (2013)
  • H. HäGerström et al.

    Low-Frequency Dielectric Spectroscopy as a Tool for Studying the Compatibility between Pharmaceutical Gels and Mucous Tissue

    J. Pharm. Sci.

    (2003)
  • M. Hanada et al.

    Predicting physical stability of ternary amorphous solid dispersions using specific mechanical energy in a hot melt extrusion process

    Int. J. Pharm.

    (2018)
  • S. Huang et al.

    Processing thermally labile drugs by hot-melt extrusion: The lesson with gliclazide

    Eur. J. Pharm. Biopharm.

    (2017)
  • L.-D. Iftimi et al.

    Edible solid foams as porous substrates for inkjet-printable pharmaceuticals

    Eur. J. Pharm. Biopharm.

    (2019)
  • K. Ilyés et al.

    The applicability of pharmaceutical polymeric blends for the fused deposition modelling (FDM) 3D technique: Material considerations–printability–process modulation, with consecutive effects on in vitro release, stability and degradation

    Eur. J. Pharm. Sci.

    (2019)
  • A. Isreb et al.

    3D printed oral theophylline doses with innovative ‘radiator-like’ design: Impact of polyethylene oxide (PEO) molecular weight

    Int. J. Pharm.

    (2019)
  • A. Ito et al.

    Prediction of recrystallization behavior of troglitazone/polyvinylpyrrolidone solid dispersion by solid-state NMR

    Int. J. Pharm.

    (2010)
  • I. Ivanisevic

    Physical stability studies of miscible amorphous solid dispersions

    J. Pharm. Sci.

    (2010)
  • D.K. Jha et al.

    Thermodynamic aspects of the preparation of amorphous solid dispersions of Naringenin with enhanced dissolution rate

    Int. J. Pharm.

    (2020)
  • R. Jog et al.

    Solid state drug-polymer miscibility studies using the model drug ABT-102

    Int. J. Pharm.

    (2016)
  • V.R. Kallakunta et al.

    Stable amorphous solid dispersions of fenofibrate using hot melt extrusion technology: Effect of formulation and process parameters for a low glass transition temperature drug

    J. Drug Deliv. Sci. Technol.

    (2020)
  • A. Kapourani et al.

    Evaluation of rivaroxaban amorphous solid dispersions physical stability via molecular mobility studies and molecular simulations

    Eur. J. Pharm. Sci.

    (2021)
  • K. Kawakami et al.

    Calorimetric investigation of the structural relaxation of amorphous materials: Evaluating validity of the methodologies

    J. Pharm. Sci.

    (2005)
  • F. Kesisoglou et al.

    Development of In Vitro–In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls

    J. Pharm. Sci.

    (2015)
  • K. Khougaz et al.

    Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers

    J. Pharm. Sci.

    (2000)
  • T. Kissel et al.

    ABA-triblock copolymers from biodegradable polyester A-blocks and hydrophilic poly(ethylene oxide) B-blocks as a candidate for in situ forming hydrogel delivery systems for proteins

    Adv. Drug Deliv. Rev., Recent Dev. Hydrogels

    (2002)
  • G. Adam et al.

    On the Temperature Dependence of Cooperative Relaxation Properties in Glass-Forming Liquids

    J. Chem. Phys.

    (1965)
  • S.M. Alshahrani et al.

    Stability-enhanced Hot-melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus® and HPMCAS-HF

    AAPS PharmSciTech

    (2015)
  • S. Alshehri et al.

    Potential of solid dispersions to enhance solubility, bioavailability, and therapeutic efficacy of poorly water-soluble drugs: newer formulation techniques, current marketed scenario and patents

    Drug Deliv.

    (2020)
  • S. Alshehri et al.

    Rat palatability, pharmacodynamics effect and bioavailability of mefenamic acid formulations utilizing hot-melt extrusion technology

    Drug Dev. Ind. Pharm.

    (2019)
  • B.B. Alsulays et al.

    Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole

    Drug Dev. Ind. Pharm.

    (2017)
  • D. Amrol

    Single-dose azithromycin microsphere formulation: a novel delivery system for antibiotics

    Int. J. Nanomedicine

    (2007)
  • Arrhenius, S., 1889. Über die Reaktionsgeschwindigkeit bei der Inversion von Rohrzucker durch Säuren. Wilhelm...
  • E.A. Ashour et al.

    Hot Melt Extrusion as an Approach to Improve Solubility, Permeability, and Oral Absorption of a Psychoactive Natural Product

    Piperine. J. Pharm. Pharmacol.

    (2016)
  • Baert, L.E.C., Verreck, G., Thoné, D., 2006. Antifungal compositions with improved bioavailability....
  • A. Bagde et al.

    Formulation of topical ibuprofen solid lipid nanoparticle (SLN) gel using hot melt extrusion technique (HME) and determining its anti-inflammatory strength

    Drug Deliv. Transl. Res.

    (2019)
  • Banerjee, R., Manna, S., Augsburger, J., 2014. Biodegradable polymer based microimplant for ocular drug delivery....
  • S.S. Bansal et al.

    Enthalpy relaxation studies of two structurally related amorphous drugs and their binary dispersions

    Drug Dev. Ind. Pharm.

    (2010)
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