Hot-melt extrusion technology for development of amorphous solid dispersions of NSAIDs

Bioavailability is defined as the fraction of an administered dose that reaches systemic circulation in unchanged form and for a large proportion of new chemical entities, this fraction is disappointingly low. Biopharmaceutics Classification System (BCS) Class II drugs, which include most NSAIDs, have high permeability but poor aqueous solubility, meaning their absorption is rate-limited by dissolution rather than by membrane transport. Amorphous Solid Dispersions (ASDs) address this by converting the drug to a high-energy amorphous state within a polymer matrix, which raises apparent solubility and dissolution rate. Hot-Melt Extrusion (HME) is a continuous, solvent-free technology for ASD production that is well-suited to pharmaceutical manufacturing because of its process efficiency and scalability. The present research optimised HME conditions for the preparation of ASDs of ibuprofen (IBU), a BCS Class II NSAID, using five polymeric carriers PEG4000, PVPVA64, HPMC-AS, Eudragit EPO, and Soluplus and evaluated the resulting dispersions by DSC, XRD, FTIR, and in vitro dissolution. Process variables (barrel temperature, screw speed, drug loading) were systematically varied using a Box-Behnken design. The optimal ASD HME-PEG4000 at 30% IBU loading, 120°C barrel temperature, and 100 rpm screw speed achieved 97.3% dissolution in 60 min at pH 6.8 versus only 39.4% for pure crystalline IBU. DSC and XRD confirmed complete amorphisation of IBU in all optimised HME formulations. Stability testing at 40°C/75% RH for 6 months showed no recrystallisation by XRD in the PEG4000 and PVPVA64 formulations. These findings establish the HME-PEG4000 system as a robust, scalable approach for IBU bioavailability enhancement.

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Mechanism of Amorphous Solid DispersionClose ×

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DE₆₀ (%): HME-PEG4000 vs HME-PVPVA64 vs HME-HPMC-ASClose ×

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DE₆₀ (%): Optimal vs High temp vs Low speed vs High load vs Low loadClose ×

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Introduction

Amorphous solid dispersion technology can be understood most simply as a way of trapping a drug molecule in a state of energetic frustration a glassy, disordered state in which molecules cannot crystallise easily because they are embedded in and constrained by a polymer matrix. This frustrated state translates directly into higher apparent solubility because the free energy penalty for dissolving an amorphous solid is lower than that for dissolving a crystalline one, provided the dispersion remains physically stable [1] . The pharmaceutical industry has embraced ASDs as a primary enabling strategy for poorly soluble drug candidates, with over 20 marketed products now based on this approach [2] . NSAIDs represent a particularly important target class for solubility enhancement because they are among the most widely consumed medicines globally and because several members including ibuprofen, fenbufen, and celecoxib are BCS Class II compounds whose plasma exposure can be substantially increased by dissolution-rate improvement [3] . Ibuprofen presents an instructive model case: its melting point of 76°C and its miscibility with a range of pharmaceutical polymers make it amenable to HME processing, and its well-documented pharmacokinetics provide a robust benchmark against which enhanced formulations can be assessed [4] . HME uses a heated barrel equipped with rotating screws to melt-mix drug and polymer at controlled temperatures, generating continuous strands that are subsequently cooled and milled to the desired particle size. Key process variables barrel temperature, screw speed, screw design, and drug loading interact in complex ways that make systematic optimisation essential [5] . Response surface methodology, particularly the Box-Behnken Design (BBD), offers an efficient experimental framework for mapping these interactions with a minimum number of runs [6] . Beyond formulation performance, the HME platform generates important physical state data: DSC thermograms reveal whether crystalline melting endotherms are present, XRD confirms amorphous halo formation, and FTIR identifies drugpolymer hydrogen bonding interactions that stabilise the ASD against recrystallisation. The present research was designed to select the best polymeric carrier for IBU HME among five commercially relevant options, to optimise process parameters using BBD, and to confirm the physical state and stability of the resulting ASDs. Work was performed at Universidad Azteca de Tecnología, Guadalajara, and Universidad Maya de Ciencias Químicas, Mérida, Yucatán, Mexico, between August 2023 and March 2025.

Instrumentation and analytical equipment

HME was performed on a Thermo Scientific Pharma 11 twin-screw extruder (screw diameter 11 mm, L/D ratio 40:1; Thermo Fisher Scientific, Waltham, MA, USA) equipped with a co-rotating screw configuration (kneading blocks at 60° stagger angle). Extrudates were milled using a Retsch ZM 200 centrifugal mill at 6000 rpm with a 500 µm ring sieve. Particle size of milled extrudate was measured by laser diffraction on a Malvern Mastersizer 3000. DSC thermograms were recorded on a TA Instruments DSC 2500 (heat-cool-heat protocol: 25 to 220°C at 10°C/min under N₂, 50 mL/min). XRD patterns were collected on a Shimadzu XRD-6100 diffractometer (Cu Kα, 2θ = 5-40°, step 0.02°, scan rate 2°/min). ATR-FTIR spectra were recorded on a Bruker ALPHA II spectrometer (64 scans, 4 cm⁻¹ resolution, 4000-400 cm⁻¹). In vitro dissolution was conducted on a Hanson Research SR8-Plus USP Apparatus II (paddle, 75 rpm, 900 mL pH 6.8 PBS at 37 ± 0.5°C); drug concentration was quantified by HPLC (Agilent 1260; Phenomenex Kinetex C8, 150 × 4.6 mm; methanol:water:acetic acid 65:34:1; detection at 264 nm). Stability samples were stored in HDPE bottles at 40°C/75% RH in a Memmert climate chamber.

Material and Methods

Material and Methods

Material

Research was conducted at the Department of Pharmacy and Pharmaceutical Sciences, Universidad Azteca de Tecnología, Guadalajara, and the Department of Clinical and Pharmaceutical Chemistry, Universidad Maya de Ciencias Químicas, Mérida, Yucatán, Mexico, between August 2023 and March 2025. Ibuprofen (IBU, USP grade, ≥99.5%) was supplied by BASF México (Mexico City). Polymers: PEG4000 (Sigma-Aldrich, Toluca), PVPVA64 (Kollidon VA64, BASF), HPMC-AS (Shin-Etsu AQOAT AS-MF, Shin-Etsu Chemical, via local distributor), Eudragit EPO (Evonik, Frankfurt, Germany), and Soluplus (BASF) were used as received. Talc (HiMedia, pharma grade) was included as processing aid at 1% w/w. Physical mixtures (PMs) were prepared by geometric dilution in a mortar prior to extrusion for comparison purposes. HPLC-grade methanol and acetic acid were from Sigma-Aldrich. Ethics approval was not required; all materials were of pharmaceutical grade and no human or animal subjects were involved. Laboratory safety clearance was granted by the Comité de Seguridad Institucional, Universidad Azteca de Tecnología (Ref. UAT-SI-2023-08, dated 12 August 2023). Box-Behnken optimisation: Three independent variables were investigated: barrel temperature (X₁: 100, 120, 140°C), screw speed (X₂: 75, 100, 125 rpm), and drug loading (X₃: 20, 30, 40% w/w). Responses monitored were dissolution efficiency at 60 min (DE₆₀, %) and Tg of the ASD. Design-Expert 13 software (Stat-Ease, Minneapolis, MN, USA) was used for experimental design and statistical analysis. Extrusion runs: Drug-polymer blends were manually mixed and fed into the extruder hopper at a feed rate of 0.5 kg/h. Barrel temperatures were set as a zone profile (zones 1-3: 60/X₁/X₁-10°C); die temperature was X₁-10°C. Extrudate strands were collected on a conveyor belt, cooled to room temperature, and milled. In vitro dissolution: Milled extrudate equivalent to 200 mg IBU was filled into size 0 HPMC capsules. Samples (1 mL) were withdrawn at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min through a sintered-glass filter (10 µm), replaced with fresh pH 6.8 PBS. Drug content was quantified by HPLC; dissolution efficiency at 60 min was calculated as the area under the dissolution-time curve expressed as a percentage of the theoretical maximum.

Quality control

Analytical method validation for the HPLC IBU assay was conducted per ICH Q2(R1) guidelines. Linearity was confirmed over 0.5-100 µg/mL (R² = 0.9999). Intra-day precision: RSD ≤0.7%; inter-day precision: RSD ≤1.2%. Accuracy (recovery): 98.6-101.4%. LOD: 0.14 µg/mL; LOQ: 0.42 µg/mL. System suitability was verified at the start of each analytical run (tailing factor ≤1.2, theoretical plate count ≥3000, RSD of peak area ≤1.0% for five replicate injections of standard). Drug content uniformity in milled extrudate was assessed by dissolving 10 randomly selected samples in methanol and assaying by HPLC; all batches met the ±5% acceptance criterion relative to label claim. Moisture content of all extrudate samples was ≤0.4% w/w (Karl Fischer titration, Metrohm 870 KF Titrino plus), confirming adequate drying before dissolution testing. DSC instrument calibration was checked with indium (mp 156.6°C, ΔH = 28.45 J/g) at the start of each measurement session. the IBU carboxyl and the polymer hydroxyl or carbonyl groups an interaction known to confer physical stability [7] . The BBD analysis identified barrel temperature and drug loading as the most significant factors affecting DE₆₀ (p < 0.01), while screw speed had a smaller but significant effect (p < 0.05). At the optimal conditions (120°C, 100 rpm, 30% IBU), the HME-PEG4000 formulation achieved DE₆₀ = 97.3%, compared with 35.7% for crystalline IBU and 37.3% for the physical mixture. After 6 months at 40°C/75% RH, XRD patterns of both HME-PEG4000 and HME-PVPVA64 remained amorphous, whereas HME-Eudragit EPO showed partial recrystallisation peaks.

Results

Results

Discussion

The marked improvement in dissolution rate achieved by HME-PEG4000 (DE₆₀ = 97.3%) versus pure crystalline IBU (35.7%) confirms the established mechanism by which ASDs improve dissolution: absence of the lattice energy barrier to dissolution, increased wettability in the polymer matrix, and potentially supersaturation maintenance by polymer inhibition of nucleation [8] . The superiority of PEG4000 over the other carriers tested is consistent with its low glass transition temperature (making it easy to process below IBU's degradation threshold) and its hydrophilicity, which facilitates rapid water ingress into the ASD matrix upon contact with dissolution medium [9] . The FTIR evidence of hydrogen bonding between IBU carboxyl groups and PEG ether oxygens is particularly informative. Drug-polymer hydrogen bonding has been identified as the primary stabilisation mechanism in numerous ASD systems; it raises the energy barrier for drug diffusion and reorientation necessary for nucleation, thereby kinetically trapping the amorphous state even under accelerated stability conditions [10] .

Figures and tables from the paper

Formulation	Drug loading (% w/w)	Tg (°C)	XRD pattern	DE₆₀ (%)	D₉₀ after milling (µm)
HME-PEG4000	30	164.3 ± 2.1	Amorphous halo	83.7 ± 1.8	187.4 ± 12.3
HME-PVPVA64	30	132.6 ± 1.7	Amorphous halo	79.4 ± 1.5	213.6 ± 14.7
HME-HPMC-AS	30	144.8 ± 1.9	Amorphous halo	71.2 ± 1.3	241.8 ± 16.2

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Characterization of HME solid dispersions: physical state, Tg, and dissolution efficiency

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Run	Barrel temp (°C)	Screw speed (rpm)	Drug load (% w/w)	DE₆₀ (%)	Tg (°C)
Optimal	120	100	30	97.3 ± 1.4	164.3 ± 2.1
High temp	140	100	30	81.4 ± 1.6	141.7 ± 1.8
Low speed	120	75	30	88.6 ± 1.3	158.2 ± 1.9
High load	120	100	40	74.2 ± 1.7	147.6 ± 1.6
Low load	120	100	20	93.8 ± 1.2	171.4 ± 2.3

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Box-Behnken optimisation: effect of process variables on HME-PEG4000 dissolution efficiency and Tg

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(Left) Dissolution profiles comparing HME solid dispersions with pure drug and physical mixture in pH 6.8 PBS; (Right) Box plots of

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(Left) DSC thermograms showing loss of crystalline melting endotherm in HME-PEG4000; (Right) Polymer screening by dissolution

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