Determination of Stable Co-Amorphous Drug-Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures

Co-amorphous drug–drug systems have been developed with the overall aim of improving the physical stability of two or more amorphous drugs. Co-amorphous systems often show good physical stability, and higher solubility and dissolution rates compared to their crystalline counterparts. The aim of this study is to determine if eutectic mixtures of two drugs can form stable co-amorphous systems. Three drug–drug mixtures, indomethacin–naproxen (IND−NAP), nifedipine–paracetamol (NIF−PAR), and paracetamol–celecoxib (PAR−CCX), were investigated for their eutectic and co-amorphization behavior as well as their physical stability in the co-amorphous form. The phase diagrams of the crystalline mixtures and the thermal behavior of the co-amorphous systems were analyzed by differential scanning calorimetry. The solid-state form and physical stability of the co-amorphous systems were analyzed using X-ray powder diffractometry during storage at room temperature at dry conditions. Initial eutectic screening using nifedipine (NIF), paracetamol (PAR), and celecoxib (CCX) indicated that IND−NAP, NIF−PAR, and PAR−CCX can form eutectic mixtures. Phase diagrams were then constructed using theoretical and experimental values. These systems, at different drug-to-drug ratios, were melted and cooled to form binary mixtures. Most mixtures were found to be co-amorphous systems, as they were amorphous and exhibited a single glass transition temperature. The stability study of the co-amorphous systems indicated differences in their physical stability. Comparing the phase diagrams with the physical stability of the co-amorphous mixtures, it was evident that the respective drug–drug ratio that forms the eutectic point also forms the most stable co-amorphous system. The eutectic behavior of drug–drug systems can thus be used to predict drug ratios that form the most stable co-amorphous systems

Polymers in pharmaceutical additive manufacturing: A balancing act between printability and product performance

Materials and manufacturing processes share a common purpose of enabling the pharmaceutical product to perform as intended. This review on the role of polymeric materials in additive manufacturing of oral dosage forms, focuses on the interface between the polymer and key stages of the additive manufacturing process, which determine printability. By systematically clarifying and comparing polymer functional roles and properties for a variety of AM technologies, together with current and emerging techniques to characterize these properties, suggestions are provided to stimulate the use of readily available and sometimes underutilized pharmaceutical polymers in additive manufacturing. We point to emerging characterization techniques and digital tools, which can be harnessed to manage existing trade-offs between the role of polymers in printer compatibility versus product performance. In a rapidly evolving technological space, this serves to trigger the continued development of 3D printers to suit a broader variety of polymers for widespread applications of pharmaceutical additive manufacturing

Glass-Transition Temperature of the β-Relaxation as the Major Predictive Parameter for Recrystallization of Neat Amorphous Drugs.

Recrystallization of amorphous drugs is currently limiting the simple approach to improve solubility and bioavailability of poorly water-soluble drugs by amorphization of a crystalline form of the drug. In view of this, molecular mobility, α-relaxation and β-relaxation processes with the associated transition temperatures Tgα and Tgβ, was investigated using dynamic mechanical analysis (DMA). The correlation between the transition temperatures and the onset of recrystallization for nine amorphous drugs, stored under dry conditions at a temperature of 296 K, was determined. From the results obtained, Tgα does not correlate with the onset of recrystallization under the experimental storage conditions. However, a clear correlation between Tgβ and the onset of recrystallization was observed. It is shown that at storage temperature below Tgβ, amorphous nifedipine retains its amorphous form. On the basis of the correlation, an empirical correlation is proposed for predicting the onset of recrystallization for drugs stored at 0% RH and 296 K

The significance of the amorphous potential energy landscape for dictating glassy dynamics and driving solid-state crystallisation.

The fundamental origins surrounding the dynamics of disordered solids near their characteristic glass transitions continue to be fiercely debated, even though a vast number of materials can form amorphous solids, including small-molecule organic, inorganic, covalent, metallic, and even large biological systems. The glass-transition temperature, Tg, can be readily detected by a diverse set of techniques, but given that these measurement modalities probe vastly different processes, there has been significant debate regarding the question of why Tg can be detected across all of them. Here we show clear experimental and computational evidence in support of a theory that proposes that the shape and structure of the potential-energy surface (PES) is the fundamental factor underlying the glass-transition processes, regardless of the frequency that experimental methods probe. Whilst this has been proposed previously, we demonstrate, using ab initio molecular-dynamics (AIMD) simulations, that it is of critical importance to carefully consider the complete PES - both the intra-molecular and inter-molecular features - in order to fully understand the entire range of atomic-dynamical processes in disordered solids. Finally, we show that it is possible to utilise this dependence to directly manipulate and harness amorphous dynamics in order to control the behaviour of such solids by using high-powered terahertz pulses to induce crystallisation and preferential crystal-polymorph growth in glasses. Combined, these findings provide compelling evidence that the PES landscape, and the corresponding energy barriers, are the ultimate controlling feature behind the atomic and molecular dynamics of disordered solids, regardless of the frequency at which they occur

Influence of Drug Load on the Printability and Solid-State Properties of 3D-Printed Naproxen-Based Amorphous Solid Dispersion

Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10–30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion

The Role of Glass Transition Temperatures in Coamorphous Drug–Amino Acid Formulations

The improved physical stability associated with coamorphous drug–amino acid (AA) formulations may indicate a decrease in mobility of the amorphous drug molecules, compared to the neat amorphous form of the drug. Since the characteristic glass transition temperatures (<i>T</i>_gα and <i>T</i>_gβ) represent molecular mobility in amorphous systems, we aimed to characterize <i>T</i>_gα and <i>T</i>_gβ and to determine their role in physical stability as well as their potential usefulness to determine the presence of an excess component (either drug or AA) in coamorphous systems. Indomethacin (IND)–tryptophan (TRP) and carvedilol (CAR)–TRP were used as model coamorphous systems. The analytical techniques used were X-ray powder diffractometry (XRPD) to determine the solid-state form, dynamic mechanical analysis (DMA) to probe <i>T</i>_gα and <i>T</i>_gβ, and differential scanning calorimetry (DSC) to probe thermal behavior of the coamorphous systems. <i>T</i>_gα analysis showed a gradual monotonous increase in <i>T</i>_gα values with increasing AA concentration, and this increase in the <i>T</i>_gα value is not the cause of the improved physical stability. The <i>T</i>_gβ analysis for the IND–TRP sample with 10% drug had a <i>T</i>_gβ of 226.8 K, and samples with 20–90% drug had similar <i>T</i>_gβ values around 212.5 K. For CAR–TRP, samples with 10–40% drug had similar <i>T</i>_gβ values around 230.5 K, and samples with 50–90% drug had similar <i>T</i>_gβ values around 223.3 K. The similar <i>T</i>_gβ values in coamorphous systems at different drug ratios indicate that they in fact are the <i>T</i>_gβ of the component that is in excess to an ideal drug–AA coamorphous mixture. DSC and XRPD analysis showed that for IND–TRP, IND is in excess if the drug concentration is 30% or above and will eventually recrystallize. For CAR–TRP, CAR is in excess and recrystallizes when the drug concentration is 50% or above. We have proposed a means of estimating, on the basis of <i>T</i>_gβ, which drug to AA ratios will lead to optimally physically stable coamorphous systems that can be considered for further development