Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development
Abstract
Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.
Introduction
The oral route of drug administration is regarded as the most preferred route for medicines, with more than 85% of drugs sold around the world being administered orally. In this context, the properties of a drug molecule that govern oral absorption are critical to its development. The Biopharmaceutics Classification System (BCS) serves as a guide to predict oral absorption based on the aqueous solubility and permeability of a drug [1,2]. Poor solubility is among the primary causes of low bioavailability for orally administered drugs. Drugs that are slightly soluble to practically insoluble exhibit solubility of ≤0.01% based on the description in the United States Pharmacopoeia (USP) [3]. In a comparison of solubility of 200 oral drugs of various origin as seen in Figure 1, 40–45% were very slightly soluble to practically insoluble, representing 33% of drugs listed in the US Pharmacopeia and 75% of compounds under development and 90% of new chemical entities were regarded as poorly soluble [4,5,6,7,8,9,10,11]. The improvement of solubility is therefore regarded as a key driver for greater bioavailability.
The Noyes–Whitney equation [12] relates mass transfer to the concentration gradient as
dM / dt = DA[Cs−Ct] / h
where D is the diffusion coefficient (cm2/s), A is the cross-sectional area, h is the thickness of the hydrodynamic diffusion layer and Cs is the solubility or maximum concentration. Under infinite dilution (sink), the concentration gradient approximates to solubility Cs, resulting in
dM / dt = DACs / h
For poorly soluble drugs, increasing aqueous solubility and the surface area are primary means of increasing the rate and extent of dissolution since parameters D and h are a function of extrinsic factors such as viscosity of dissolution medium and stirring rate. The approaches to improve dissolution rate may be broadly classified as physical and chemical as shown in Table 1.
Among these approaches, the conversion of drugs into an amorphous solid dispersion (ASD) form has gained widespread attention over the last few decades. The ASD of a drug molecularly dispersed in a polymeric matrix has been extensively utilized to improve solubility and bioavailability of poorly soluble drugs [19,25,26,27]. An ASD of vemurafenib (Zelboraf®) increased human bioavailability by about five-fold compared to the crystalline form [19]. However, since amorphous forms are thermodynamically unstable, the materials and technologies that enable ASD formation, the subsequent dosage form and the methods of characterization of these systems play a critical role in defining the quality, stability, processability and in-vivo performance of the ASD. There are over forty successfully launched ASD-based drug products in the market that point to an industrial relevance and increasing maturity and robustness of the ASD approach as seen from Figure 2. In this paper, the authors discuss the various aspects associated with development of ASDs from a molecule to a medicine including challenges associated with transfer from a laboratory set-up to commercial manufacturing and the need for novel polymers that enable ASD-based medicinal dosage forms.
| Drug (Marketed Product) | Technology (1) | Polymer (2) | Dissolution Approach (3) FDA Recommended Method ( #9884; ) vs. Bio-Relevant Approach (∞) | Supporting Analytical Techniques | Conclusion |
|---|---|---|---|---|---|
| Reference product of Verapamil: ISOPTIN-SRE, ER tablets Developed formulation (tablets) [93] | HME (ISOPTIN-SRE) Kneading, solvent and co-precipitation method | HPMC/HPC 12 SDs prepared: 1:1, 1:2 and 1:3 API—polymer ratios with the following polymers: PVPK30, β-cyclodextrin, PEG 6000, HPMCK100M | #9884; Two-phase dissolution: phase 1: 900 mL SGF without enzyme 60 min; phase 2: withdraw and transfer to 900 mL SIF without enzyme, 7 h 50 rpm, USP II with wire helix ∞Phosphate buffer pH 1.2, 900 mL, 50 rpm, USP I | DSC, PXRD, SEM, FTIR, supersaturation solubility testing, stability studies | Increased dissolution rates of tablets containing SD with API: PEG6000 ratio of 1:3 in comparison to other formulations and marketed tablets due to decreased particle size, increased wettability and dispersibility of verapamil; Drug–carrier interaction observed; Higher polymer concentration gives faster drug release. |
| Reference product of Itraconazole: Sporanox cps, and ONMEL tbl Developed formulation (SD, tablets) [94] | Spray lavering (Sporanox) HME (ONMEL) Solubilization in concentrated aqueous solutions of weak organic acids and drying | HPMC SDs with 2–20% drug load prepared with Glutaric acid | #9884; 0.1 N HCl, 900 mL 75 rpm, USP II (tbl) SGF without enzyme, 900 mL, 100 rpm, USP II (cps) ∞0.1 N HCL, 250 mL 75 rpm, USP II (ASD) | DSC, PXRD, ATR-FTIR, pH-solubility studies | Solubility greatly enhanced compared to amorphous form of drug, possible weak drug–acid interactions observed; precipitated as mostly nanoparticles that enable rapid re-dissolution, which might influence absorption. |
| Reference product of Tacrolimus PROGRAF Developed formulation (SD) [95] | Spray drying/fluid bed (PROGRAF) Spray drying via solvent-evaporation method, solvent-wetting method, or surface-attached method – three different processing methodologies | HPMC 3SDs prepared: 10:80:1 API:HP-β-CD:DOSS ratio | #9884; 0.005% HPC in Water with 0.50% SLS adjusted to pH 4.5, 900 mL, 100 rpm, USP II (tbl) #9884; HPC solution (1 in 20,000), adjusted to pH 4.5 by phosphoric acid, 900 mL 50 rpm, USP II (cps) ∞0.005% HPC in Water with 0.50% SLS adjusted to pH 4.5 by phosphoric acid, 500 mL 50 rpm, USP II with sinker (SD) | SEM, DSC, PXRD | The solubility and dissolution were significantly improved by SD preparation method compared to drug powder. |
| Reference product of Nifedipine Afeditab Developed Tablets [96] | Melt/absorb on carrier Co-precipitation | Poloxamer or PVP 12 SDs prepared:1:1, 1:5 and 1:10 API:polymer ratio with all listed polymers: poloxamer, HPMC, PEG 4000 and PEG 6000 [36]; with each API-Polymer ratios of 1:1, 1:5 and 1:10 tested | #9884; 0.5% SLS in SGF without enzyme pH 1.2, 900 mL 100 rpm, USP II (tbl ER) #9884; SGF without enzyme, 900 mL 50 rpm, USP II (cps) ∞SGF without enzyme, 900 mL 50 rpm, USP XXI (SD, tbl) | DSC, FT-IR | SD tablets prepared with PEG 6000 and poloxamer showed better release profile than marketed products. |
| Reference product of Griseofulvin (Gris-PEG) Developed formulation (SD) [97] | HME (Gris-PEG) Solvent evaporation technique | PEG 6000 24 SDs prepared: 3:1, 1:1, 1:2 and 1:9 API:polymer ratios with all polymers: PVP, HPMC, and Eudragit L 100, Eudragit E 100, Eudragit S 100, PEG 8000 | #9884; 4.0% SLS in water, 1000 mL 75 rpm, USP II (tbl) #9884; 0.54% SLS in water, 1000 mL 25 an 50 rpm, USP II (susp) ∞Dissolution studies not performed. | PXRD, mDSC, ATR-IR, Raman spectroscopy | Increased polymer concentration leads to lower drug released because drug binds tighter to the concentrated polymers, however SD is more stable. |
| Reference product of Nimodipine Nimotop Developed formulation (SD) [98] | Spray drying (Nimotop) HME | PEG 9 SDs prepared: 1:2, 3:7 and 1:9 API:polymer ratio with polymers: HPMC, PVP-VA, Eudragit EPO | #9884; 0.5% SDS in water, 900 mL 50 rpm, USP II (cps) ∞0.05% SLS in acetate buffer pH 4.5, 900 mL 75 rpm, ZRS-8G (paddle) | DSC, XRPD, FT-IR, SEM | Eudragit EPO and PVP-VA showed better miscibility than HPMC. Drug–polymer hydrogen bonding was observed. |
| Reference formulation of Lopinavir & Ritonavir KALETRA tablets and capsules Developed formulation (SD) [99] | HME (KALETRA) Solvent granulation process | PVP-VA SDs with various API1:API2:PVP-VA ratios | #9884; Tier 1:0.06 M polyoxyethyelene 10 lauryl ether with 10 mM sodium phosphate monobasic (pH 6.8) #9884; Tier 2: same as tier 1 with no more than 1750 USP units/L of pancreatin, 900 mL (cps) 50 rpm, USP II #9884; Test 1: 0.06 M decaethyelene glycolmonododecyl ether in water #9884; Test 2: 37.7 g/L of polyoxyethyelene 10-lauryl ether in water (tbl) 75 rpm, USP II ∞10 mM phosphate buffer pH 6.8, 250 mL and 0.1 N HCl, 250 mL 150 rpm, jacketed beaker | XRPD, FT-IR | Molecular mixing of both components into a single amorphous phase negatively impacts ritonavir dissolution performance in comparison with marketed formulation. Amorphous suppression phenomenon observed in pH-shift dissolution method. It is proposed that dissolution of ritonavir from the surface of the particles in acidic media leaves behind a lopinavir-rich surface which acts as a barrier for the remaining ritonavir to dissolve. |
| Reference product of Fenofibrate Fenoglide Developed formulation (SD) [100] | HME (Fenoglide) Solvent evaporation method | PEG/Poloxamer 188 7 SDs prepared: 1:1, 1:2 and 1:3 API:polymer ratio with polymers: Carplex 80 and PEG 4000 and 1:5:6 API:polymer ratio with Carplex 80 and PEG 6000 respectively | #9884; 25 mM/50 mM/0.75% SLS in water, 1000/1000/900 mL (40 and 120 mg/48 and 145 mg/54 and 160 mg tbl) 50/50/75 rpm, USP II #9884; Phosphate buffer w/2% Tween 80 and 0.1% pancreatin pH 6.8, 900 mL 75 rpm, USP II (cps) ∞Demineralized water, 900 mL 50 rpm, USP II | DSC, PXRD, FT-IR, SEM | The most significant improvement of drug dissolution and amorphization was obtained with SD prepared with drug:Carplex:PEG ratio 1:5:6 |
| Reference product of Ivacaftor KALYDECO Developed formulation (SD) [101] | Spray drying (KALYDECO) HME | HPMCAS 9 SDs prepared: 1:1 API: polymer (Soluplus, HPMC, Copovidone), each pair with three surfactants (SLS, poloxamer, polysorbate 70) | #9884; 50 mM sodium phosphate buffer with 0.7% SLS pH 6.8, 900 mL (tbl) 65 rpm, USP II with a sinker ∞50 mM sodium phosphate buffer pH 6.8, 900 mL 65 rpm, USP II | XRPD, DSC, FT-IR | Improved solubilization by improved wetting of drug substance by hydrophilic carriers which represent rich microenvironment formed at the surface of the drug substance and this leads to improved dissolution rate. No defined drug–polymer interaction was observed. |
| Reference product of Posaconazole Noxafil Developed formulation (SD, tablets) [102] | HME (Noxafil) Spray drying | HPMCAS 1 SD prepared: 3:1 API:polymer ratio with polymer Eudragit L100 | #9884; Acid Stage: 0.01 N HCl, 750 mL; Buffer Stage: 50 mM phosphate buffer, pH 6.8 with 0.37% Polysorbate 80 (after 120 min, to the acid stage, add 250 mL of 0.2 M Phosphate Buffer, 1.46% Polysorbate 80) (tbl DR) 75 rpm, USP II #9884; 0.3% SLS, 900 mL 25 rpm, USP II (susp) ∞0.01 M HCl with 34 mM NaCl solution and phosphate buffer with SIF powder pH 6.5 CTD apparatus | mDSC, PXRD, SEM, in-vivo study | The in-vitro dissolution data underpredicted in-vivo performance, potentially due to higher driving force for precipitation in-vitro versus in-vivo. Including a concentration-sustaining polymer extragranularly to SD but inside tablet was as effective as including it inside the ASD itself. |
| Reference product of Everolimus CERTICAN and ZORTRESS Developed formulation (SD, tablets) [103] | Melt or spray drying (CERTICAN, ZORTRESS) Solvent-wetting and co-precipitation methods | HPMC SDs with various API:polymer ratios with HPMC were prepared | #9884; Water with 0.4% sodium dodecylsulfate, 500 mL (tbl) 50 rpm, USP II ∞0.4% SLS solution in water and distilled water, dissolution media pH 1.2, pH 4.0 and pH 6.8, 900 mL 50 rpm, USP II | XRPD, SEM, particle size analysis, stability and in-vivo studies | The optimized SD consisted of drug:HPMC weight ratio of 1:15. Tablets with SD created with solvent-wetting technique showed identical release rate to that of commercially available product. |
| Reference formulation of Telaprevir INCIVEK Developed formulation (SD) [104] | Spray drying (INCIVEK) Co-milling with polymers | HPMCAS 3 SDs prepared: 1:1 API:polymer ratio with polymers: PVP-K30, PEG 6000, HPMC | #9884; 1% SLS in water, 900 mL (tbl) 50 rpm, USP II ∞Distilled water, 0.1 M HCl pH 1.2, phosphate buffer pH 6.8, 900 mL 100 rpm, ZRC-8D (paddle) | XRPD, DSC, SEM, FT-IR, cytotoxicity evaluation, stability studies | Hydrogen bonding drug–polymer interaction observed. Drug–polymer SD did not affect efficacy of the drug and showed no toxic side effects to normal liver cells. No comparison to reference product shown. |
| Reference formulation of Vemurafenib ZELBORAF Developed formulation (SD, capsules) [19] | Co-precipitation method (ZELBORAF) Co-precipitation method | HPMCAS 3 SDs prepared: 2:3 API:polymer ratio with HPMCP, HPMCAS, and Eudragit L 100-55 | #9884; 1% Hexadecyltrimethylammonium bromide in 0.05 M phosphate buffer pH 6.8, 900 mL (tbl) 75 rpm, USP II ∞0.05% hexadecyltrimethylammonium bromide in phosphate buffer pH 6.8 10 mL/min, USP IV ∞FaSSIF, 900 mL 75 rpm, USP II [101] | XRPD, DSC, SEM, stability and in-vivo studies | Among used polymers, HPMCAS was found to be the best to prepare stable SD, based on superior physical stability and faster dissolution. No dissolution comparison to reference product shown. |
| Reference product of Ritonavir NORVIR HIV Developed formulation (SD) [105] | HME (NORVIR HIV) Solvent evaporation and melt method | PVP-VA 4 SDs prepared: 1:4 API:polymer ratio polymers Gelucire, sorbitol (with both listed method): | #9884; 60 mM polyoxyethyelene 10 lauryl ether, 900 mL (tbl) 75 rpm, USP II #9884; 0.1 M HCl with 25 mM polyoxyethyelene 10-lauryl ether (cps) 50 rpm, USP II ∞0.1 M HCl, 900 mL FaSSIF pH 6.5, 500 mL ∞FeSSIF pH 5.0, 1000 mL 50 rpm, USP II with sinkers | DSC, XRPD, TEM, FT-IR, in-vivo study | Hydrogen bonding was observed in SD resulting in increased drug solubility as compared to pure drug. Maximum dissolution was obtained with FeSSIF media, which confirmed food-related absorption of drugs. No comparison to reference product available. |
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Iyer, R.; Petrovska Jovanovska, V.; Berginc, K.; Jaklič, M.; Fabiani, F.; Harlacher, C.; Huzjak, T.; Sanchez-Felix, M.V. Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development. Pharmaceutics 2021, 13, 1682. https://doi.org/10.3390/pharmaceutics13101682