Hydrophobic Active Pharmaceutical Ingredients Research Articles

Data-Driven Design of Novel Polymer Excipients for Pharmaceutical Amorphous Solid Dispersions.

About 90% of active pharmaceutical ingredients (APIs) in the oral drug delivery system pipeline have poor aqueous solubility and low bioavailability. To address this problem, amorphous solid dispersions (ASDs) embed hydrophobic APIs within polymer excipients to prevent drug crystallization, improve solubility, and increase bioavailability. There are a limited number of commercial polymer excipients, and the structure-function relationships which lead to successful ASD formulations are not well-documented. There are, however, certain solid-state ASD characteristics that inform ASD performance. One characteristic shared by successful ASDs is a high glass transition temperature (Tg), which correlates with higher shelf stability and decreased drug crystallization. We aim to identify how polymer features such as side chain geometry, backbone methylation, and hydrophilic-lipophilic balance impact Tg to design copolymers capable of forming high-Tg ASDs. We tested a library of 50 ASD formulations (18 previously studied and 32 newly synthesized) of the model drug probucol with copolymers synthesized through automated photoinduced electron/energy transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization. A machine learning (ML) algorithm was trained on the Tg data to identify the major factors influencing Tg, including backbone methylation and nonlinear side chain geometry. In both polymer alone and probucol-loaded ASDs, a Random Forest Regressor captured structure-function trends in the data set and accurately predicted Tg with an average R2 > 0.83 across a 10-fold cross validation. This ML model will be used to predict novel copolymers to design ASDs with high Tg, a crucial factor in predicting ASD success.

Synthesis and supramolecular behavior study of a novel amphiphilic compound for idebenone encapsulation

The synthesis of a new amphiphilic compound obtained from galactose and glycerol monostearate is described, applying an efficient and environmentally friendly technique as is click reactions. The physicochemical characterization was carried out using nuclear magnetic resonance and high resolution mass spectrometry. Indeed, the novel compound enhances the solubility of idebenone, a hydrophobic active pharmaceutical ingredient. Transmission electron microscopy and molecular dynamics simulation were used to visualize the self-aggregated molecules, and dynamic light scattering to analyze the size of the supramolecular structure that shows nano-sized aggregates, with dimensions of up to 200 nm. The cytotoxicity and biocompatibility assay using murine macrophage RAW 264.7 cells showed no cytotoxicity at the 0.1 and 0.05 mg/ml concentration tested. Water solubility of idebenone increased sixteen-fold in the presence of the synthesized compound. Idebenone loading suggests that amphiphilic compound could be used as a potential drug delivery system in medicinal applications.

Orthogonal Gelations to Synthesize Core-Shell Hydrogels Loaded with Nanoemulsion-Templated Drug Nanoparticles for Versatile Oral Drug Delivery.

Hydrophobic active pharmaceutical ingredients (APIs) are ubiquitous in the drug development pipeline, but their poor bioavailability often prevents their translation into drug products. Industrial processes to formulate hydrophobic APIs are expensive, difficult to optimize, and not flexible enough to incorporate customizable drug release profiles into drug products. Here, a novel, dual-responsive gelation process that exploits orthogonal thermo-responsive and ion-responsive gelations is introduced. This one-step "dual gelation" synthesizes core-shell (methylcellulose-alginate) hydrogel particles and encapsulates drug-laden nanoemulsions in the hydrogel matrices. In situ crystallization templates drug nanocrystals inside the polymeric core, while a kinetically stable amorphous solid dispersion is templated in the shell. Drug release is explored as a function of particle geometry, and programmable release is demonstrated for various therapeutic applications including delayed pulsatile release and sequential release of a model fixed-dose combination drug product of ibuprofen and fenofibrate. Independent control over drug loading between the shell and the core is demonstrated. This formulation approach is shown to be a flexible process to develop drug products with biocompatible materials, facile synthesis, and precise drug release performance. This work suggests and applies a novel method to leverage orthogonal gel chemistries to generate functional core-shell hydrogel particles.

Effect of nano graphene oxide (nGO) incorporation on the lipophilicity of hydrophobic drugs

Lipophilicity is a measure of partitioning of an active pharmaceutical ingredient (API) in a lipophilic phase and has been shown to affect gastrointestinal absorption. If a hydrophobic API is completely water insoluble; it does not dissolve in the aqueous phase and is not available for absorption in the gastrointestinal (GI) lipid layer. Therefore, an optimum lipophilicity is important for enhanced bioavailability. It is typically measured as logP or log (Octanol-Water partition coefficient). While water soluble drugs tend to have negative values, high logP can be a problem with insoluble drugs. There are no strict guidelines on logP for hydrophobic drugs, but typically a logP between 0 and 2 is desirable. In this paper, we represent the lowering of logP of hydrophobic API via the successful incorporation of 0.5–2.0% of nanographene oxide (nGO). Four hydrophobic drugs namely Griseofulvin (GF), Dexamethasone (DXM), Apixaban (APX) and Megestrol Acetate (MA) were tested at physiological/intestine pH of 6.0, 7.0, and 8.0 to estimate partitioning behavior. The increased nGO incorporation led to the substantial decrease in logP of all the nGO formulated drugs at all pH as compared to pure drugs. In the cases of GF, APX and MA, the logP decreased from over 2.0 to somewhere between 1.0 and 2.0, and for DXM these decreased to negative values thus making it behave like a water soluble API. The maximum decrease in logP for DXM, GF, APX and MA were 157, 54, 61 and 64% respectively. In summary, the nGO incorporation is an effective means to lower logP and may significantly lead to improved biological absorption and therapeutic efficacy. We believe that current study is very promising for improving efficacy and potentially lowering drug dosage.

Microfluidic encapsulation of enzymes and steroids within solid lipid nanoparticles

The production of solid lipid nanoparticles (SLNs) is challenging, especially when considering the incorporation of biologics. A novel in-house method of microfluidic production of biologic-encapsulated SLNs is proposed, using a variety of base materials for formulation to help overcome the barriers presented during manufacture and administration. Trypsin is used as a model drug for hydrophilic encapsulation whilst testosterone is employed as a positive non-biologic lipophilic control active pharmaceutical ingredient. Particle sizes obtained ranged from 160 to 320 nm, and a lead formulation has been identified from the combinations assayed, allowing for high encapsulation efficiencies (47–90%, respectively) of both the large hydrophilic and the small hydrophobic active pharmaceutical ingredients (APIs). Drug release profiles were analysed in vitro to provide useful insight into sustained kinetics, providing data towards future in vivo studies, which displayed a slow prolonged release for testosterone and a quicker burst release for trypsin. The study represents a large leap forward in the field of SLN production, especially in the field of difficult-to-encapsulate molecules, and the technique also benefits from being more environmentally sustainable due to the use of microfluidics.Graphical

Templated Reactive Crystallization of Active Pharmaceutical Ingredient in Hydrogel Microparticles Enabling Robust Drug Product Processing

Commercialization of most promising active pharmaceutical ingredients (APIs) is impeded either by poor bioavailability or challenging physical properties leading to costly manufacture. Bioavailability of ionizable hydrophobic APIs can be enhanced by its conversion to salt form. While salt form of the API presents higher solution concentration than the non-ionized form, poor physical properties resulting from particle anisotropy or non-ideal morphology (needles) and particle size distribution not meeting dissolution rate targets can still inhibit its commercial translation. In this regard, API physical properties can be improved through addition of non-active components (excipients or carriers) during API manufacture. In this work, a facile method to perform reactive crystallization of an API salt in presence of the microporous environment of a hydrogel microparticle is presented. Specifically, the reaction between acidic antiretroviral API, raltegravir and base potassium hydroxide is performed in the presence of polyethylene glycol diacrylamide hydrogel microparticles. In this bottom-up approach, the spherical template hydrogel microparticles for the reaction lead to monodisperse composites loaded with inherently micronized raltegravir-potassium crystals, thus improving API physical properties without hampering bioavailability. Overall, this technique provides a novel approach to reactive crystallization while maintaining the API polymorph and crystallinity.

Encapsulation of PI3K Inhibitor LY294002 within Polymer Nanoparticles Using Ion Pairing Flash Nanoprecipitation.

Flash nanoprecipitation (FNP) is a turbulent mixing process capable of reproducibly producing polymer nanoparticles loaded with active pharmaceutical ingredients (APIs). The nanoparticles produced with this method consist of a hydrophobic core surrounded by a hydrophilic corona. FNP produces nanoparticles with very high loading levels of nonionic hydrophobic APIs. However, hydrophobic compounds with ionizable groups are not as efficiently incorporated. To overcome this, ion pairing agents (IPs) can be incorporated into the FNP formulation to produce highly hydrophobic drug salts that efficiently precipitate during mixing. We demonstrate the encapsulation of the PI3K inhibitor, LY294002, within poly(ethylene glycol)-b-poly(D,L lactic acid) nanoparticles. We investigated how incorporating two hydrophobic IPs (palmitic acid (PA) and hexadecylphosphonic acid (HDPA)) during the FNP process affected the LY294002 loading and size of the resulting nanoparticles. The effect of organic solvent choice on the synthesis process was also examined. While the presence of either hydrophobic IP effectively increased the encapsulation of LY294002 during FNP, HDPA resulted in well-defined colloidally stable particles, while the PA resulted in ill-defined aggregates. The incorporation of hydrophobic IPs with FNP opens the door for the intravenous administration of APIs that were previously deemed unusable due to their hydrophobic nature.

3D-Powder-Bed-Printed Pharmaceutical Drug Product Tablets for Use in Clinical Studies.

Printing of phase 1 and 2a clinical trial formulations represents an interesting industrial application of powder bed printing. Formulations for clinical trials are challenging because they should enable flexible changes in the strength of the dosage form by varying the active pharmaceutical ingredient (API) percentage and tablet mass. The aim of this study was to investigate how powder bed 3D printing can be used for development of flexible platforms for clinical trials, suitable for both hydrophilic and hydrophobic APIs, using only conventional tableting excipients. A series of pre-formulation and formulation studies were performed to develop two platform formulations for clinical trials using acetaminophen and diclofenac sodium as model compounds and lactose and starch as excipients. The results showed that the type of starch used as the formulation binder must be optimized based on the type of API. Moreover, powder blend flow and liquid penetration ability proved to be critical material attributes (CMAs) that need to be controlled, particularly at high drug loading. Optimization of these CMAs was performed by selecting the appropriate particle size of the API or by addition of silica. A critical process parameter that had to be controlled for production of tablets of good quality was the quantity of the printing ink. After optimization of both the formulation and process parameters, two platform formulations, that is, one for each API, were successfully developed. Within each platform, drug loading from 5 up to 50% w/w and tablet mass from 50 to 500 mg were achieved. All 3D-printed tablets could be produced at tensile strength above 0.2 MPa, and most tablets could enable immediate release (i.e., >80% w/w within 30 min).

Microfluidic Particle Engineering of Hydrophobic Drug with Eudragit E100─Bridging the Amorphous and Crystalline Gap.

Co-processing active pharmaceutical ingredients (APIs) with excipients is a promising particle engineering technique to improve the API physical properties, which can lead to more robust downstream drug product manufacturing and improved drug product attributes. Excipients provide control over critical API attributes like particle size and solid-state outcomes. Eudragit E100 is a widely used polymeric excipient to modulate drug release. Being cationic, it is primarily employed as a precipitation inhibitor to stabilize amorphous solid dispersions. In this work, we demonstrate how co-processing of E100 with naproxen (NPX) (a model hydrophobic API) into monodisperse emulsions via droplet microfluidics followed by solidification via solvent evaporation allows the facile fabrication of compact, monodisperse, and spherical particles with an expanded range of solid-state outcomes spanning from amorphous to crystalline forms. Low E100 concentrations (≤26% w/w) yield crystalline microparticles with a stable NPX polymorph distributed uniformly across the matrix at a high drug loading (∼89% w/w). Structurally, E100 incorporation reduces the size of primary particles comprising the co-processed microparticles in comparison to neat API microparticles made using the same technique and the as-received API powder. This reduction in primary particle size translates into an increased internal porosity of the co-processed microparticles, with specific surface area and pore volume ∼9 times higher than the neat API microparticles. These E100-enabled structural modifications result in faster drug release in acidic media compared to neat API microparticles. Additionally, E100-NPX microparticles have a significantly improved flowability compared to neat API microparticles and as-received API powder. Overall, this study demonstrates a facile microfluidics-based co-processing method that broadly expands the range of solid-state outcomes obtainable with E100 as an excipient, with multiscale control over the key attributes and performance of hydrophobic API-laden microparticles.

INFLUENCE OF THE LIPID COMPOSITION ON THE PROPERTIES, TECHNOLOGY AND QUALITY INDICATORS OF LIPOSOMAL DRUGS

Liposomal drug delivery system is an example of the use of nanodrugs in medical practice. Encapsulation of active pharmaceutical ingredients in liposomal nanoparticles allows increasing their bioavailability and efficacy. Aim. The article is devoted to the analysis of the lipid composition of liposomal drugs developed in Ukraine, its influence on the choice of technology and control parameters. Results. The lipid compositions of liposomal drugs developed in Ukraine in recent years were reviewed. The advantages and disadvantages of natural phosphatidylcholine as the main membrane-forming lipid were analyzed. Data on the influence of anionic phospholipids and cholesterol in the liposomal membrane composition on the stability of liposomal nanoparticles and the level of active pharmaceutical ingredient encapsulation were given. The main technological stages of obtaining liposomes with hydrophilic and hydrophobic active pharmaceutical ingredients were considered. The main groups of quality indicators of liposomal dosage forms have been determined. Conclusions. The lipid composition determines the structure and physicochemical properties of the lipid membrane, the mechanism and level of active pharmaceutical ingredient encapsulation, which significantly influences the pharmacological efficacy of liposomal drug delivery systems.

Nanoemulsions Containing Megestrol Acetate: Development, Characterization, and Stability Evaluation.

Many active pharmaceutical ingredients (API) are poorly soluble in water and their low oral bioavailability is a major hindrance to their potential use. Megestrol acetate (MGA) is insoluble in water and its oral absorption is limited and considerably affected by food. Nanoemulsions (NEs) can be used as effective oral drug delivery systems where the hydrophobic API is loaded into the oil phase. In this study, MGA-loaded NEs were prepared based on the spontaneous emulsification technique. The effects of different excipients such as ethanol, Tween 80, Lipoid E80, and medium-chain triglyceride (MCT) on the NEs characterization were investigated. The experimental results indicated that optimum MGA-loaded NEs (F20) were nanometer-sized droplets (166.9 ± 3.0 nm) with negative zeta potential (-12.2 ± 1.1 mV). The effect of polyvinylpyrrolidone (PVP) on characteristic properties of F20 was also evaluated. On the selected NEs, in vitro dissolution tests and stability studies in various mediums and storage conditions were performed. The encapsulation efficiency of NEs were > 99%. The overall droplet size of F20 and PVP-2 (PVP-coated NEs) remained relatively stable as the pH changed from 1.2 to 6.8. It was determined that F20 and PVP-2 remained stable at 4°C until 12 weeks and had higher cytotoxicity on MCF-7 cells. To conclude, droplet size, surface charge, and stability are important properties for NEs to have sufficient effectiveness. In this study, alternative oral NEs of low-solubility drug MGA were developed considering the above features.

Promotion of the anticancer activity of curcumin based on a metal–polyphenol networks delivery system

Curcumin (Cur), a hydrophobic active pharmaceutical ingredient with high anticancer activity, has poor water solubility and low bioavailability. Although many delivery systems have been developed to improve their bioavailability, some limitation such as low drug loading efficiency and poor stability are still remained. The metal-polyphenol networks (MPNs) delivery system designed in this subject solved above problems and effectively improved the anticancer activity of Cur. The synthesized Cur@EGCG-Fe(III) is consisting of epigallocatechin gallate (EGCG), iron chloride (FeCl3) and Cur, and the well-designed structure endow Cur@EGCG-Fe(III) high loading efficiency, good water solubility and stability. After the Cur@EGCG-Fe(III) nanoparticles were internalized by MCF-7 cells, the Cur could be released in endo/lysosomal microenvironment (pH = 5.0), and the Cur delivery in the deep tumor could be realized. The distribution of Cur@EGCG-Fe(III) in MCF-7 cells was analyzed by laser confocal, and Cur@EGCG-Fe(III) could effectively deliver more Cur into MCF-7 cells in comparison with free Cur. In addition, the results of flow cytometry and western blot further indicated that Cur@EGCG-Fe(III) had a stronger ability to induce apoptosis than free Cur. Transwell cell migration and invasion experiments showed that Cur and EGCG-Fe(III) had a synergistic effect in inhibiting MCF-7 cell migration and invasion. In vitro hemolysis and in vivo experiments showed that the Cur@EGCG-Fe(III) had negligible effect on the blood environment and a great tumor-inhibition efficacy, indicating that the MPNs delivery system had a good blood compatibility and antitumor activity. Our results indicated that MPNs-coated Cur nanoparticle could be a new form of Cur delivery system for anticancer application.

"QUALITY BY DESIGN" IN LIPOSOMAL DRUGS CREATION

Nanobiotechnological preparations creation is one of the promising areas of modern pharmacy, since it allows creating products of a qualitatively new level. The procedure development, based on an understanding of the product characteristics and the technological process, confirmed by reliable scientific data. The article is devoted to the pharmaceutical development of liposomal drugs. On the basis of our own experience in the development of liposomal medicinal forms, as well as on the basis of literature data, the main components in their composition were detected and these components impact on the quality indicators of liposomes were studied. Individual lipids function in nanoparticle membrane and their interaction, which determines the stability both in the technological process and upon storage of the product, were considered. The advantages and disadvantages of cholesterol incorporation into liposomes with hydrophilic and hydrophobic active pharmaceutical ingredients were described. Cryoprotectors and buffer systems role in ensuring nanopreparation stability is discussed.

Occurrence and prevention of Pickering foams in pharmaceutical nano-milling

Particle size reduction to sub-micrometer dimensions in stirred media mills is an increasingly common formulation strategy used for improving the bioavailability of poorly aqueous soluble active pharmaceutical ingredients (APIs). Due to their hydrophobic character, the API particles need to be stabilised by a surfactant in order to form a stable nano-suspension. This work is concerned with the understanding of an undesired phenomenon often encountered during the development and scale-up of wet nano-milling processes for hydrophobic APIs – the formation of foams. We investigate the microstructure, rheology and stability of these foams, and find them to be Pickering foams stabilised by solid particles at the gas-liquid interface rather than by a surfactant. By exploring the effect of surfactant concentration on the on-set of foaming in conjunction with the milling kinetics, we find a relationship between the specific surface area of the nano-suspension, the quantity of surfactant present in the formulation and the occurrence of foaming. We propose a mechanistic explanation of foam formation, and find that in order to prevent foaming, a large surfactant excess of approx. 100x above the critical micelle concentration has to be present in the solution in order to ensure a sufficiently rapid coverage of freshly exposed hydrophobic surfaces formed during the wet nano-milling process.

Spray-Dried Succinylated Soy Protein Microparticles for Oral Ibuprofen Delivery.

The potential value of succinylated soy protein (SPS) as a wall material for the encapsulation of ibuprofen (IBU), a model hydrophobic drug, by spray-drying was investigated. A succinylation rate of 93% was obtained for soy protein isolate, with a molar ratio of 1/1.5 (NH2/succinic anhydride). The solubility profile at 37°C showed that this chemical modification decreased the solubility of the protein below its isoelectric point, whereas solubility increased in alkaline conditions. Various SPS/IBU ratios (90/10, 80/20, and 60/40) were studied and compared with the same ratio of soy protein isolate (SPI/IBU). High encapsulation efficiency was achieved (91-95%). Microparticles were spherical and between 4 and 8μm in diameter. The spray-drying of protein/IBU solutions appeared to be beneficial, as it resulted in an amorphous solid dispersion of IBU within the microparticles, coupled with an increase in the thermal stability of IBU. In vitro release was evaluated in acidic (pH1.2 in the presence of pepsin) and neutral (pH6.8) conditions similar to those in the gastrointestinal (GI) tract. IBU was released significantly more slowly at pH1.2, for both proteins. However, this slowing was particularly marked for SPS, for which rapid (within 2h) and complete release was observed at pH6.8. These results validate the hypothesis that SPS is suitable for use as a coating material for hydrophobic active pharmaceutical ingredients (APIs) due to its pH sensitivity, which should delay IBU release in the gastrointestinal tract.

Photocurable Bioinks for the 3D Pharming of Combination Therapies.

Combination therapies mediate drug synergy to improve treatment efficacy and convenience, leading to higher levels of compliance. However, there are challenges with their manufacturing as well as reduced flexibility in dosing options. This study reports on the design and characterization of a polypill fabricated through the combination of material jetting and binder jetting for the treatment of hypertension. The drugs lisinopril and spironolactone were loaded into hydrophilic hyaluronic acid and hydrophobic poly(ethylene glycol) (PEG) photocurable bioinks, respectively, and dispensed through a piezoelectric nozzle onto a blank preform tablet composed of two attachable compartments fabricated via binder jetting 3D printing. The bioinks were photopolymerized and their mechanical properties were assessed via Instron testing. Scanning electron microscopy (SEM) was performed to indicate morphological analysis. The polypill was ensembled and drug release analysis was performed. Droplet formation of bioinks loaded with hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) was achieved and subsequently polymerized after a controlled dosage was dispensed onto preform tablet compartments. High-performance liquid chromatography (HPLC) analysis showed sustained release profiles for each of the loaded compounds. This study confirms the potential of material jetting in conjunction with binder jetting techniques (powder-bed 3D printing), for the production of combination therapy oral dosage forms involving both hydrophilic and hydrophobic drugs.

Bioinspired co-crystals of Imatinib providing enhanced kinetic solubility

Realizing the full potential of co-crystals enhanced kinetic solubility demands a comprehensive understanding of the mechanisms of dissolution, phase conversion, nucleation and crystal growth, and of the complex interplay between the active pharmaceutical ingredient (API), the coformer and co-existing forms in aqueous media. One blueprint provided by nature to keep poorly water-soluble bases in solution is the complexation with phenolic acids. Consequently, we followed a bioinspired strategy for the engineering of co-crystals of a poorly water-soluble molecule – Imatinib – with a phenolic acid, syringic acid (SYA). The dynamics of dissolution and solution-mediated phase transformations were monitored by Nuclear Magnetic Resonance (NMR) spectroscopy, providing mechanistic insights into the 60 fold-increased long lasting concentrations achieved by the syringate co-crystals as compared to Imatinib base and Imatinib mesylate. This lasting effect was linked to SYA’s ability to delay the formation and nucleation of Imatinib hydrate – the thermodynamically stable form in aqueous media – through a metastable association of SYA with Imatinib in solution. Results from permeability studies evidenced that SYA did not impact Imatinib’s permeability across membranes while suggesting improved bioavailability through higher kinetic solubility at the biological barriers. These results reflect that some degree of hydrophobicity of the coformer might be key to extend the kinetic solubility of co-crystals with hydrophobic APIs. Understanding how kinetic supersaturation can be shaped by the selection of an interactive coformer may help achieving the needed performance of new forms of poorly water-soluble, slowly dissolving APIs.

Photocurable poly(ethylene glycol) as a bioink for the inkjet 3D pharming of hydrophobic drugs

Binder jetting and material extrusion are the two most common additive manufacturing techniques used to create pharmaceutical tablets. However, their versatility is limited since the powder component is present throughout the dosage forms fabricated by binder jet 3D printing and material extrusion 3D printing requires high operating temperatures. Conversely, material jetting allows for compositional control at a voxel level and can dispense material at room temperature. Unfortunately, there are a limited number of materials that are both printable and biocompatible. Therefore, the aim of this study was to engineer photocurable bioinks that are suitable for hydrophobic active pharmaceutical ingredients and have rapid gelation times upon visible light exposure. The resulting bioinks were comprised of poly(ethylene glycol) diacrylate (250 Da) as the crosslinkable monomer, Eosin Y as the photoinitiator, and methoxide-poly(ethylene glycol)-amine as the coinitiator. Additionally, poly(ethylene glycol) (200 Da) was added as a plasticizer to modulate the drug release profiles, and Naproxen was used as the model drug due to its high hydrophobicity. Various bioink formulations were dispensed into the bottom half of blank preform tablets – made via direct compression – using a piezoelectric nozzle, photopolymerized, and capped with the top half of the preform tablet to complete the pharmaceutical dosage form. Results from the release studies showed that drug release can be modulated by both the percent of poly(ethylene glycol) diacrylate in the formulation and the light exposure time used to cure the bioinks. These bioinks have the potential to expand the library of materials available for creating pharmaceutical tablets via inkjet printing with personalized drug dosages.

Application of Ultra-Centrifugation and Bench-Top 19F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products.

Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field 19F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol® lots was 32 ± 3% with 1% variation from method reproducibility test. The partition results were 52 ± 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol® but by a different process. The significant difference in DFPN-phase partition between Durezol® and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation and 19F NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control.

Advances in Polymer Design for Enhancing Oral Drug Solubility and Delivery.

Synthetic polymers have enabled amorphous solid dispersions (ASDs) to emerge as an oral delivery strategy for overcoming poor drug solubility in aqueous environments. Modern ASD products noninvasively treat a range of chronic diseases (for example, hepatitis C, cystic fibrosis, and HIV). In such formulations, polymeric carriers generate and maintain drug supersaturation upon dissolution, increasing the apparent drug solubility to enhance gastrointestinal barrier absorption and oral bioavailability. In this Review, we outline several approaches in designing polymeric excipients to drive interactions with active pharmaceutical ingredients (APIs) in spray-dried ASDs, highlighting polymer-drug formulation guidelines from industrial and academic perspectives. Special attention is given to new commercial and specialized polymer design strategies that can solubilize highly hydrophobic APIs and suppress the propensity for rapid drug recrystallization. These molecularly customized excipients and hierarchical excipient assemblies are promising toward informing early-stage drug-discovery development and reformulating existing API candidates into potentially lifesaving oral medicines for our growing global population.