PE and PET oligomers' interplay with membrane bilayers.

The prevalence of microplastic pollution in nature and foodstuffs is fairly well identified. However, studies of micro- or nanoplastics' cell membrane permeation and health effects in humans are lacking. Our study focuses on examining the interactions of polyethylene (PE) and polyethylene terephthalate (PET) with bilayer membranes. We have performed molecular dynamics simulations to study how plastic oligomers behave in bilayers. In addition, we have studied membrane permeation of PE and Bis(2-hydroxyethyl) terephthalate (BHET), a type of PET monomer, with Parallel Artificial Membrane Permeability Assay (PAMPA). As a result, in simulations the molecules exhibited different movements and preferred locations in membrane. PAMPA studies suggested similar preferences in membrane, especially for PE plastic. Our results suggest that passive diffusion could be an important transport mechanism into cells for some small plastic oligomers. Both molecular dynamics simulations and PAMPA have potential for micro- and nanoplastics research.

Co-Amorphous Formulations of Furosemide with Arginine and P-Glycoprotein Inhibitor Drugs.

In this study, the amino acid arginine (ARG) and P-glycoprotein (P-gp) inhibitors verapamil hydrochloride (VER), piperine (PIP) and quercetin (QRT) were used as co-formers for co-amorphous mixtures of a Biopharmaceutics classification system (BCS) class IV drug, furosemide (FUR). FUR mixtures with VER, PIP and QRT were prepared by solvent evaporation, and mixtures with ARG were prepared by spray drying in 1:1 and 1:2 molar ratios. The solid-state properties of the mixtures were characterized with X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) in stability studies under different storage conditions. Simultaneous dissolution/permeation studies were conducted in side-by-side diffusion cells with a PAMPA (parallel artificial membrane permeability assay) membrane as a permeation barrier. It was observed with XRPD that ARG, VER and PIP formed co-amorphous mixtures with FUR at both molar ratios. DSC and FTIR revealed single glass transition values for the mixtures (except for FUR:VER 1:2), with the formation of intermolecular interactions between the components, especially salt formation between FUR and ARG. The co-amorphous mixtures were found to be stable for at least two months under an elevated temperature/humidity, except FUR:ARG 1:2, which was sensitive to humidity. The dissolution/permeation studies showed that only the co-amorphous FUR:ARG mixtures were able to enhance both the dissolution and permeation of FUR. Thus, it is concluded that formulating co-amorphous salts with ARG may be a promising option for poorly soluble/permeable FUR.

Preparation and characterization of hot-melt extruded polycaprolactone-based filaments intended for 3D-printing of tablets.

Hot-melt extruded (HME) filaments are an essential intermediate product for the three- dimensional (3D) printing of drug delivery systems (DDSs) by the fused deposition modelling (FDM) process. The aim of this study was to design novel polymeric 3D-printable HME filaments loaded with active pharmaceutical ingredients (APIs). The physical solid-state properties, mechanical properties, drug release and short-term storage stability of the filaments and 3D-printed DDSs were studied. Physical powder mixtures of polycaprolactone (PCL), plasticizer and API were manually blended, extruded by a single-screw extruder, and printed by a table-top FDM 3D-printing system. The composition of PCL and arabic gum (ARA) enabled the incorporation of 20%, 30% and 40% (w/w) of indomethacin (IND) and theophylline (THEO) into the HME filaments. The uneven distribution of API throughout the filaments impaired 3D printing. The HME filaments loaded with 20% IND or THEO were selected for the further analysis and printing tests (the ratio of PCL, ARA and IND or THEO was 7:1:2, respectively). The IND filaments were yellowish, mechanically strong and flexible, and they had a uniform filament diameter and smooth outer surface. The filaments containing THEO were smooth and off-white. The 3D-printed tablets fabricated from IND or THEO-loaded filaments showed sustained drug release in vitro. The drug release rate, however, significantly increased by changing the geometry of 3D-printed tablets from a conventional tablet structure to an unorthodox lattice ("honeycomb") structure. Overall, the combination of PCL and ARA provides an interesting novel polymeric carrier system for 3D-printable HME filaments and tablets.

Dissolution and Permeability Properties of Co-Amorphous Formulations of Hydrochlorothiazide.

A biopharmaceutics classification system class IV drug, hydrochlorothiazide (HCT), was combined with co-formers of L-and d-arginine (ARG) and sodium lauryl sulphate (SLS) by cryomilling in 1:1 molar ratio. Co-amorphization was observed with L- and D-ARG. These mixtures showed a single glass transition, evidence of possible salt formation and improved physical stability at elevated temperatures and/or humidity when compared with amorphous HCT. The co-amorphous formulations, along with the combinations of HCT and HCT:L-ARG with polyvinylpyrrolidone (PVP) in 1:1 mass ratio, were investigated with a simultaneous dissolution/permeation setup using parallel artificial membrane permeability assay (PAMPA) or Madine Darby kidney cells (MDCKII) as the permeation barrier. It was observed that co-amorphization with L-ARG and D-ARG was able to induce a supersaturated state for HCT, possibly through intermolecular interactions, but there was virtually no difference between the dissolution properties of the mixtures formed with the 2 optical isomers of ARG. The permeability of HCT was found to be dependent on the dissolution properties of the formulations in both PAMPA and cellular barrier experiments. Thus, co-amorphization of HCT with L- and D-ARG demonstrated the possibility to enhance the dissolution and thereby the permeation potential of a BCS class IV drug.

The effect of co-amorphization of glibenclamide on its dissolution properties and permeability through an MDCKII-MDR1 cell layer.

Co-amorphous mixtures have been demonstrated to represent a promising approach for enhancing the dissolution of poorly water-soluble drugs. However, little is known of their permeability properties, especially through biological membranes, or about the relationship between their dissolution and permeability. In the present study, co-amorphous glibenclamide (GBC) mixtures with two amino acids, arginine (ARG) and serine (SER), in molar ratios of 1:1 were prepared by cryomilling. Their dissolution and permeability properties were studied in side-by-side diffusion chambers using cell layers containing Madine Darby kidney cells overexpressing P-glycoprotein (Pgp) transporters (MDCKII-MDR1), as Pgp may influence the absorption of GBC. Furthermore, two other compounds, the flavonoid quercetin (QRT) which is a Pgp inhibitor and the surfactant, sodium lauryl sulfate (SLS), were used as excipients to investigate if they improved either passive or active diffusion of GBC. In addition, amorphous QRT and a co-amorphous mixture of GBC and QRT (1:1) were characterized with respect to their solid-state properties and physical stability. It was demonstrated that co-amorphous GBC mixtures exhibited superior dissolution properties over the corresponding physical mixtures and amorphous GBC. Furthermore, the co-amorphous GBC-ARG-SLS mixture exhibited a 9-fold increase in permeating through the MDCKII-MDR1 cell layer as compared to the corresponding physical mixture. There was a correlation between the dissolution and permeability area under curve (AUC) values, evidence that the main mechanism behind the improved permeability of co-amorphous mixtures was their improved dissolution. The simultaneous dissolution/permeation testing with side-by-side diffusion chambers and MDCKII-MDR1 cells proved to be a feasible method for evaluating the dissolution/permeation interplay of amorphous compounds.

Preparation and characterization of multi-component tablets containing co-amorphous salts: Combining multimodal non-linear optical imaging with established analytical methods.

Co-amorphous mixtures have rarely been formulated as oral dosage forms, even though they have been shown to stabilize amorphous drugs in the solid state and enhance the dissolution properties of poorly soluble drugs. In the present study we formulated tablets consisting of either spray dried co-amorphous ibuprofen-arginine or indomethacin-arginine, mannitol or xylitol and polyvinylpyrrolidone K30 (PVP). Experimental design was used for the selection of tablet compositions, and the effect of tablet composition on tablet characteristics was modelled. Multimodal non-linear imaging, including coherent anti-Stokes Raman scattering (CARS) and sum frequency/second harmonic generation (SFG/SHG) microscopies, as well as scanning electron microscopy, X-ray diffractometry and Fourier-transform infrared spectroscopy were utilized to characterize the tablets. The tablets possessed sufficient strength, but modelling produced no clear evidence about the compaction characteristics of co-amorphous salts. However, co-amorphous drug-arginine mixtures resulted in enhanced dissolution behaviour, and the PVP in the tableting mixture stabilized the supersaturation. The co-amorphous mixtures were physically stable during compaction, but the excipient selection affected the long term stability of the ibuprofen-arginine mixture. CARS and SFG/SHG proved feasible techniques in imaging the component distribution on the tablet surfaces, but possibly due to the limited imaging area, recrystallization detected with x-ray diffraction was not detected.

Permeability of glibenclamide through a PAMPA membrane: The effect of co-amorphization.

Co-amorphous systems are an attractive alternative for amorphous solid polymer dispersions in the formulation of poorly soluble drugs. Several studies have revealed that co-amorphous formulations can enhance the dissolution properties of poorly-soluble drugs and stabilize them in the amorphous form. However, the interplay between the drug dissolution rate, drug supersaturation and different co-formers on membrane permeability of the drug for co-amorphous formulations remains unexplored. By using side-by-side chambers, separated by a PAMPA (parallel artificial membrane permeability assay) membrane, we were able to simultaneously test dissolution and passive membrane permeability of the co-amorphous combinations (1:1 molar ratio) of a poorly soluble drug glibenclamide (GBC) in combination with two amino acids, either serine (SER) or arginine (ARG). In addition, a known passive permeability enhancer sodium lauryl sulfate (SLS) was included in the co-amorphous mixtures at two concentration levels. The mixtures were also characterized with respect to their solid-state properties and physical stability. It was found that GBC mixtures with ARG and SLS had superior dissolution and physical stability properties which was attributable to the strong intermolecular interactions formed between GBC and ARG. These formulations also had optimal permeability properties due to their high concentration gradient promoting permeation and possible permeation enhancing effect of the co-formers ARG and SLS. Thus, simultaneous testing of dissolution and permeation through a PAMPA membrane may represent a simple and inexpensive tool for screening the most promising amorphous formulations in further studies.

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations.

Amorphous solid dispersions (ASDs) are probably the most common and important supersaturating drug delivery systems for the formulation of poorly water-soluble compounds. These delivery systems are able to achieve and maintain a sustained drug supersaturation which enables improvement of the bioavailability of poorly water-soluble drugs by increasing the driving force for drug absorption. However, ASDs often require a high weight percentage of carrier (usually a hydrophilic polymer) to ensure molecular mixing of the drug in the carrier and stabilization of the supersaturated state, often leading to high dosage volumes and thereby challenges in the formulation of the final dosage form. As a response to the shortcomings of the ASDs, the so-called co-amorphous formulations, which are amorphous combinations of two or more low molecular weight components, have emerged as an alternative formulation strategy for poorly-soluble drugs. While the current research on co-amorphous formulations is focused on preparation and characterization of these systems, more detailed research on their supersaturation and precipitation behavior and the effect of co-formers on nucleation and crystal growth inhibition is needed. The current status of this research is reviewed in this paper. Furthermore, the potential of novel preparation methods for co-amorphous systems with respect to the current preparation methods are discussed.

Spray drying of poorly soluble drugs from aqueous arginine solution.

Co-amorphous drug-amino acid mixtures have shown potential for improving the solid-state stability and dissolution behavior of amorphous drugs. In previous studies, however these mixtures have been produced mainly with small-scale preparation methods, or with methods that have required the use of organic solvents or other dissolution enhancers. In the present study, co-amorphous ibuprofen-arginine and indomethacin-arginine mixtures were spray dried from water. The mixtures were prepared at two drug-arginine molar ratios (1:1 and 1:2). The properties of the prepared mixtures were investigated with differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and a 24h, non-sink, dissolution study. All mixtures exhibited a single glass transition temperature (Tg), evidence of the formation of homogenous single-phase systems. Fourier transform infrared spectroscopy revealed strong interactions (mainly salt formation) that account for the positive deviation between measured and estimated Tg values. No crystallization was observed during a 1-year stability study in either 1:1 or 1:2 mixtures, but in the presence of moisture, handling difficulties were encountered. The formation of co-amorphous salts led to improved dissolution characteristics when compared to the corresponding physical mixtures or to pure crystalline drugs.

Reflectometric monitoring of the dissolution process of thin polymeric films.

Pharmaceutical thin films are versatile drug-delivery platforms i.e. allowing transdermal, oral, sublingual and buccal administration. However, dissolution testing of thin films is challenging since the commonly used dissolution tests for conventional dosage forms correspond rather poorly to the physiological conditions at the site of administration. Here we introduce a traditional optical reflection method for monitoring the dissolution behavior of thin polymeric films. The substances, e.g. drug molecules, released from the film generate an increase in the refractive index in the liquid medium which can be detected by reflectance monitoring. Thin EUDRAGIT® RL PO poly(ethyl acrylate-co-methyl methacrylate-co trimethylammonioethyl methacrylate chloride) (RLPO) films containing the model drug perphenazine (PPZ) were prepared by spraying on a glass substrate. The glass substrates were placed inside the flow cell in the reflectometer which was then filled with phosphate buffer solution. Dissolution was monitored by measuring the reflectance of the buffer liquid. The method was able to detect the distinctive dissolution characteristics of different film formulations and measured relatively small drug concentrations. In conclusion, it was demonstrated that a traditional optical reflection method can provide valuable information about the dissolution characteristics of thin polymeric films in low liquid volume surroundings.

Effect of storage on the physical stability of thin polymethacrylate-perphenazine films.

We evaluated the physical stability of thin polymethacrylate-drug films under three different storage conditions by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, polarized light microscopy, and Fourier transform infrared spectroscopy. Mechanical properties i.e. elongation, mechanical strength, and in vitro drug release from the thin films were also determined during storage. The films consisted of ammonium methacrylate copolymer (RLPO)/dimethylaminoethyl methacrylate copolymer (EPO), polyvinylpyrroline (PVP)/polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) and perphenazine (PPZ). PPZ remained fully amorphous in all RLPO- and EPO -films for up to 12months' storage at 4°C in dry conditions. Instead, in EPO+PVP+PPZ 15% -films, higher temperature induced recrystallization of PPZ within three months and higher humidity also at six months. Crystallization was also observed in EPO+Soluplus+PPZ 10% -films at high temperature at 12months. The amount of PPZ released was significantly lower from recrystallized PPZ films than from stable amorphous films. The better stability of RLPO -films was attributed to PPZ being molecularly dispersed and also because of strong drug-polymer interactions in the films, while increasing storage temperatures weakened the hydrogen bonding interactions in the EPO -films. In addition, the presence of hygroscopic PVP facilitated PPZ recrystallization in the EPO -films if they were stored in a highly humid environment.

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin.

Arginine, phenylalanine, and tryptophan have been previously shown to improve the solid-state stability of amorphous indomethacin. The present study investigates the ability of these amino acids to prolong the supersaturation of indomethacin in both aqueous and biorelevant conditions either when freely in solution or when formulated as co-amorphous mixtures. The co-amorphous amino acid-indomethacin mixtures (molar ratio 1:1) and amorphous indomethacin were prepared by cryomilling. Dissolution and precipitation tests were performed in buffer solutions (pH 5 and 6.5) and in Fed and Fasted State Simulated Intestinal Fluids (FeSSIF and FaSSIF, respectively). Precipitation tests were conducted with the solvent shift method. The supersaturation stability of indomethacin and the precipitation inhibitory effect of amino acids were evaluated by calculating the supersaturation factor and the excipient gain factor, respectively. Biorelevant media exerted a significant effect on indomethacin solubility but had little effect on the supersaturation stability. Arginine had the most significant impact on the dissolution properties of indomethacin, but also phenylalanine and tryptophan stabilized supersaturation in some media when formulated as co-amorphous mixtures with indomethacin. Only arginine stabilized supersaturation without co-amorphization, an effect only observed in media of pH 6.5. The unique behavior of the arginine-indomethacin mixture was further demonstrated by the abrupt formation of a precipitate, when an excess physical mixture of arginine and indomethacin was added to FeSSIF (pH 6.5). The solid-state investigation of this precipitate indicated that it probably consisted of crystalline arginine-indomethacin salt with possibly some residual crystalline starting materials.

Rational excipient selection for co-amorphous formulations.

INTRODUCTION: For almost two decades there has been intense debate about whether the amorphous solid state form could resolve the solubility problems and subsequent bioavailability issues of many small molecule drugs. Since the amorphous form is a high energy and unstable state of solid matter, any material in that form requires stabilization. Areas covered: This review examines the technologies being exploited to stabilize the amorphous state in co-amorphous formulations. The review emphasizes the importance of the appropriate selection criteria of stabilizing excipient and focuses on the mechanisms of stabilization. Expert opinion: An extensive literature review has revealed that the current research seeking to achieve stabilization of an amorphous form tends to be conducted on a case-by-case basis. This kind of approach is very inefficient since it can rarely be transferred to other cases. The greatest weakness in the selection of stabilizing excipient for co-amorphous formulations is that modern computational tools have rarely been utilized as a predictive tool in the selection of the excipient. It is evident that more research needs to be done to study larger datasets with modern in silico tools, chemometrics and advanced statistical tools to achieve a more predictive, and systematic approach for the screening of stabilizing excipients to be incorporated into co-amorphous formulations.

Characterization of Amorphous and Co-Amorphous Simvastatin Formulations Prepared by Spray Drying.

In this study, spray drying from aqueous solutions, using the surface-active agent sodium lauryl sulfate (SLS) as a solubilizer, was explored as a production method for co-amorphous simvastatin-lysine (SVS-LYS) at 1:1 molar mixtures, which previously have been observed to form a co-amorphous mixture upon ball milling. In addition, a spray-dried formulation of SVS without LYS was prepared. Energy-dispersive X-ray spectroscopy (EDS) revealed that SLS coated the SVS and SVS-LYS particles upon spray drying. X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) showed that in the spray-dried formulations the remaining crystallinity originated from SLS only. The best dissolution properties and a "spring and parachute" effect were found for SVS spray-dried from a 5% SLS solution without LYS. Despite the presence of at least partially crystalline SLS in the mixtures, all the studied formulations were able to significantly extend the stability of amorphous SVS compared to previous co-amorphous formulations of SVS. The best stability (at least 12 months in dry conditions) was observed when SLS was spray-dried with SVS (and LYS). In conclusion, spray drying of SVS and LYS from aqueous surfactant solutions was able to produce formulations with improved physical stability for amorphous SVS.

Monitoring of drug release kinetics from thin polymer films by multi-parametric surface plasmon resonance.

The aim of the present study is to monitor the release of perphenazine (PPZ) from thin polymer films in real-time by the multi-parametric surface plasmon resonance method (MP-SPR). The MP-SPR method is capable of measuring changes in polymer films that are significantly thicker than the apparent scanning depth of the SPR field. The in vitro reference measurements confirm that the MP-SPR results can be correlated to the in vitro release of PPZ. However, information gained by MP-SPR can be used to identify three different modes of change in the films with different kinetic timescales, which are not visible in the in vitro testing. The EUDRAGIT(®) RL PO-PVP-PPZ-film shows significantly faster changes than the film without polyvinylpyrroline (PVP). This information can be used to optimize the drug-release profile of different film formulations for different pharmaceutical purposes.

Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability.

Co-amorphous drug mixtures with low-molecular-weight excipients have recently been shown to be a promising approach for stabilization of amorphous drugs and thus to be an alternative to the traditional amorphous solid dispersion approach using polymers. However, the previous studies are limited to a few drugs and amino acids. To facilitate the rational selection of amino acids, the practical importance of the amino acid coming from the biological target site of the drug (and associated intermolecular interactions) needs to be established. In the present study, the formation of co-amorphous systems using cryomilling and combinations of two poorly water-soluble drugs (simvastatin and glibenclamide) with the amino acids aspartic acid, lysine, serine, and threonine was investigated. Solid-state characterization with X-ray powder diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy revealed that the 1:1 molar combinations simvastatin-lysine, glibenclamide-serine, and glibenclamide-threonine and the 1:1:1 molar combination glibenclamide-serine-threonine formed co-amorphous mixtures. These were homogeneous single-phase blends with weak intermolecular interactions in the mixtures. Interestingly, a favorable effect by the excipients on the tautomerism of amorphous glibenclamide in the co-amorphous blends was seen, as the formation of the thermodynamically less stable imidic acid tautomer of glibenclamide was suppressed compared to that of the pure amorphous drug. Furthermore, the co-amorphous mixtures provided a physical stability advantage over the amorphous drugs alone.

Refining stability and dissolution rate of amorphous drug formulations.

INTRODUCTION: Poor aqueous solubility of active pharmaceutical ingredients (APIs) is one of the main challenges in the development of new small molecular drugs. Additionally, the proportion of poorly soluble drugs among new chemical entities is increasing. The transfer of a crystalline drug to its amorphous counterpart is often seen as a potential solution to increase the solubility. However, amorphous systems are physically unstable. Therefore, pharmaceutical formulations scientists need to find ways to stabilise amorphous forms. AREAS COVERED: The use of polymer-based solid dispersions is the most established technique for the stabilisation of amorphous forms, and this review will initially focus on new developments in this field. Additionally, newly discovered formulation approaches will be investigated, including approaches based on the physical restriction of crystallisation and crystal growth and on the interaction of APIs with small molecular compounds rather than polymers. Finally, in situ formation of an amorphous form might be an option to avoid storage problems altogether. EXPERT OPINION: The diversity of poorly soluble APIs formulated in an amorphous drug delivery system will require different approaches for their stabilisation. Thus, increased focus on emerging techniques can be expected and a rational approach to decide the correct formulation is needed.

Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug-polymer mixtures.

Surface coverage may affect the crystallisation behaviour of amorphous materials. This study investigates crystallisation inhibition in powder mixtures of amorphous drug and pharmaceutical excipients. Pure amorphous indomethacin (IMC) powder and physical mixtures thereof with Eudragit(®) E or Soluplus(®) in 3:1, 1:1 and 1:3 (w/w) ratios were stored at 30 °C and 23 or 42% RH. Samples were analysed during storage by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and scanning electron microscopy (SEM). IMC Eudragit(®) mixtures showed higher physical stability than pure IMC whereas IMC Soluplus(®) mixtures did not. Water uptake was higher for mixtures containing Soluplus(®) than for amorphous IMC or IMC Eudragit(®) mixtures. However, the Tg of amorphous IMC was unaffected by the presence (and nature) of polymer. SEM revealed that Eudragit(®) particles aggregated on the surface of IMC particles, whereas Soluplus(®) particles did not. The drug particles developed multiple crystallites at their surface with subsequent crystal growth. The intimate contact between the surface agglomerated Eudragit(®) particles and drug is believed to inhibit crystallisation through reduced IMC surface molecular mobility. Polymer particles may also mechanically hinder crystal growth outwards from the surface. This work highlights the importance of microparticulate surface coverage of amorphous drug particles on their stability.

In situ amorphisation of indomethacin with Eudragit® E during dissolution.

In this study, the possibility of utilising in situ crystalline-to-amorphous transformation for the delivery of poorly water soluble drugs was investigated. Compacts of physical mixtures of γ-indomethacin (IMC) and Eudragit® E in 3:1, 1:1 and 1:3 (w/w) ratios were subjected to dissolution testing at pH 6.8 at which IMC but not the polymer is soluble. Compacts changed their colour from white to yellow indicating amorphisation of IMC. X-ray powder diffractometry (XRPD) confirmed the amorphisation and only one glass transition temperature was observed (58.1 °C, 54.4 °C, and 50.1 °C for the 3:1, 1:1 and 1:3 (w/w) drug-to-polymer ratios, respectively). Furthermore, principal component analysis of infrared spectra resulted in clustering of in situ transformed samples together with quench cooled glass solutions for each respective ratio. Subsequent dissolution testing of in situ transformed samples at pH 4.1, at which the polymer is soluble but not IMC, led to a higher dissolution rate than for quench cooled glass solution at 3:1 and 1:1 ratios, but not for the 1:3 ratio. This study showed that crystalline drug can be transformed into amorphous material in situ in the presence of a polymer, leading to the possibility of administering drugs in the amorphous state without physical instability problems during storage.

Amino acids as co-amorphous stabilizers for poorly water-soluble drugs--Part 2: molecular interactions.

The formation of co-amorphous drug-drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs--low molecular weight excipient blends--have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug.