Active Pharmaceutical Ingredients Loading Research Articles

Zeolites – tabletting ibuprofen with and without zeolites as an excipient

Abstract Introduction Drug delivery via the oral route is a patient and industry-preferred approach. However, maintaining plasma concentrations of the active pharmaceutical ingredient (API) within the therapeutic window can be challenging with immediate-release (IR) tablets. To avoid the plasma peaks and troughs associated with IR tablets, sustained release (SR) formulations have been investigated. Zeolites are microporous aluminosilicate minerals that represent a novel tabletting material with the potential for modifying drug release due to their unique adsorption and ion exchange properties1. Aim This study will investigate the potential for inclusion of zeolites within orally disintegrating tablets (ODTs) and assessment of their ability to modify API release. Methods In-house, 50%w/w ibuprofen (IBU)-loaded ODTs (IHODTs) were prepared from Pearlitol® Flash, magnesium (Mg) stearate and 2 different zeolites (CP814C and CP814E), incorporated at 5%w/w each, using a manual tablet press. Formulations were prepared and mixed for 10 minutes in a cube mixer prior to direct compression (DC) into tablets. Physical characteristics of the tablets were assessed by hardness and friability measurements. Tablet quality was assessed by disintegration and dissolution analysis to British Pharmacopeia (BP) standards2. Release profiles were assessed against various models to determine the effect of zeolites on the release of IBU. Formulations were further examined and characterised using scanning electron microscopy (SEM) and energy-dispersive x-ray (EDX) spectroscopy. An ethics evaluation was completed, and the study was identified as not having any ethical considerations by the University of South Wales. Results The mean weight of blank ODTs was found to be 225.3mg, with a mean thickness of 3.65mm, diameter of 8.10mm, hardness of 43.9±9.2N (mean±SD, n=5) and friability of 0.2±0.2% (mean±SD, n=3). The hardness of IHODTs was found to be 59.98±1.6N, reducing to 54.9±4.3N and 43.4±0.7N (mean±SD, n=3) with the inclusion of CP814C and CP814E, respectively. The friability of IHODTs containing zeolites was 1.76±0.4% and 1.91±0.9N (mean±SD, n=3), for CP814C and CP814E, respectively; conforming to BP specification2. The disintegration time for all in-house tablets, both with and without a zeolite included, was found to be an order of magnitude greater than commercial ODTs (CT) controls, but all remained within the BP specification2. The release of IBU from IHODTs and CTs showed good correlation to the first-order release model (R2 = 0.96 and 0.98, respectively), indicating IR behaviour. Similarly, the release of IBU from IHODTs containing zeolites was shown to correlate best with the first-order release model, R2 = 0.91 for CP814C and R2 = 0.90 for CP814E, respectively. SEM analysis suggested a homogeneous blend of components within IHODTs, whilst EDX analysis indicated the presence of silicon and aluminium from zeolites, and Mg and carbon from Mg stearate and IBU, respectively. Discussion / Conclusion This study investigated the effect of zeolite inclusion on the release properties of ODTs containing IBU. Although the quality of ODTs containing zeolites was not compromised, this study suggests that inclusion of a zeolite by DC only, does not significantly modify the release profile. Future studies are required to ascertain whether zeolites can achieve SR from ODTs using alternative API loading approaches, such as solvent loading1.

Orthogonal analysis reveals inconsistencies in cargo loading of extracellular vesicles.

Since extracellular vesicles (EVs) have emerged as a promising drug delivery system, diverse methods have been used to load them with active pharmaceutical ingredients (API) in preclinical and clinical studies. However, there is yet to be an engineered EV formulation approved for human use, a barrier driven in part by the intrinsic heterogeneity of EVs. API loading is rarely assessed in the context of single vesicle measurements of physicochemical properties but is likely administered in a heterogeneous fashion to the detriment of a consistent product. Here, we applied a suite of single-particle resolution methods to determine the loading of rhodamine 6G (R6G) surrogate cargo mimicking hydrophilic small molecule drugs across four common API loading methods: sonication, electroporation, freeze-thaw cycling and passive incubation. Loading efficiencies and alterations in the physical properties of EVs were assessed, as well as co-localization with common EV-associated tetraspanins (i.e., CD63, CD81 and CD9) for insight into EV subpopulations. Sonication had the highest loading efficiency, yet significantly decreased particle yield, while electroporation led to the greatest number of loaded API particles, albeit at a lower efficiency. Moreover, results were often inconsistent between repeated runs within a given method, demonstrating the difficulty in developing a rigorous loading method that consistently loaded EVs across their heterogeneous subpopulations. This work highlights the significance of how chosen quantification metrics can impact apparent conclusions and the importance of single-particle characterization of EV loading.

Development of a Semi-Mechanistic Modeling Framework for Wet Bead Milling of Pharmaceutical Nanosuspensions.

This study aimed to develop a practical semi-mechanistic modeling framework to predict particle size evolution during wet bead milling of pharmaceutical nanosuspensions over a wide range of process conditions and milling scales. The model incorporates process parameters, formulation parameters, and equipment-specific parameters such as rotor speed, bead type, bead size, bead loading, active pharmaceutical ingredient (API) mass, temperature, API loading, maximum bead volume, blade diameter, distance between blade and wall, and an efficiency parameter. The characteristic particle size quantiles, i.e., x10, x50, and x90, were transformed to obtain a linear relationship with time, while the general functional form of the apparent breakage rate constant of this relationship was derived based on three models with different complexity levels. Model A, the most complex and general model, was derived directly from microhydrodynamics. Model B is a simpler model based on a power-law function of process parameters. Model C is the simplest model, which is the pre-calibrated version of Model B based on data collected from different mills across scales, formulations, and drug products. Being simple and computationally convenient, Model C is expected to reduce the amount of experimentation needed to develop and optimize the wet bead milling process and streamline scale-up and/or scale-out.

Bottom-up production of injectable itraconazole suspensions using membrane technology

Bottom-up production of active pharmaceutical ingredient (API) crystal suspensions offers advantages in surface property control and operational ease over top-down methods. However, downstream separation and concentration pose challenges. This proof-of-concept study explores membrane diafiltration as a comprehensive solution for downstream processing of API crystal suspensions produced via anti-solvent crystallization. It involves switching the residual solvent (N-methyl-2-pyrrolidone, NMP) with water, adjusting the excipient (d-α-Tocopherol polyethylene glycol 1000 succinate, TPGS) quantity, and enhancing API loading (solid concentration) in itraconazole crystal suspensions. NMP concentration was decreased from 9 wt% to below 0.05 wt% (in compliance with European Medicine Agency guidelines), while the TPGS concentration was decreased from 0.475 wt% to 0.07 wt%. This reduced the TPGS-to-itraconazole ratio from 1:2 to less than 1:50 and raised the itraconazole loading from 1 wt% to 35.6 wt%. Importantly, these changes did not adversely affect the itraconazole crystal stability in suspension. This study presents membrane diafiltration as a one-step solution to address downstream challenges in bottom-up API crystal suspension production. These findings contribute to optimizing pharmaceutical manufacturing processes and hold promise for advancing the development of long-acting API crystal suspensions via bottom-up production techniques at a commercial scale.

Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.

Spray-dried paracetamol/polyvinylpyrrolidone amorphous solid dispersions: Part II – Solubility and in vitro drug permeation behavior

Amorphous solid dispersions (ASDs) comprising an active pharmaceutical ingredient (API) and polymer are a frequently described approach in the formulation of new drug candidates. This study aimed to evaluate the saturation solubility and dissolution behavior of ASDs consisting of paracetamol (PCM) and polyvinylpyrrolidone/vinyl acetate (PVP/VA) in water and their influence on the transepithelial in vitro permeation of PCM. With increasing amounts of PVP/VA, the water solubility of ASDs containing PCM increased up to six times compared to that of a saturated PCM solution. In the case of preparations with 30 % PCM, two-phase separation was observed in water at room temperature, consisting of a polymer-rich phase with high API loading and an aqueous, polymer-poor phase. This result was attributed to the thermoresponsive behavior of PVP/VA with lower critical solution temperature (LCST). As the PCM content in the ASD increased, the LCST decreased. This behavior was analyzed by measuring the demixing temperature (Tdem) values with differential scanning calorimetry (DSC). Furthermore, the permeation behavior of PCM from these phase-separated preparations through Caco–2 cells was analyzed. Additionally, the effect of these preparations on cell viability was evaluated using the MTT assay. Preparations with relatively high PCM concentrations showed a reduction in cell viability.

Prediction of tablet weight variability from bulk flow properties by sparse modeling

Die filling is a critical step in the pharmaceutical tableting process as it determines the uniformity in tablet weight, which affects the drug content uniformity and appearance of tablets. With the progress in powder flow characterization, a wide variety of bulk flow properties can be obtained, and several studies have been conducted to predict tablet weight variability (TWV) from bulk flow properties by applying multivariate analysis; however, there is still room for improvement in the selection of properties for predictive model construction. In this study, least absolute shrinkage and selection operator regression, a type of sparse modeling, was applied to select the critical flow properties from various ones, and TWV was predicted. To obtain blends with a wide range of properties, 27 powder blends were prepared by changing the active pharmaceutical ingredients (APIs), API loading in the formulation, and the grade of the lubricant. Bulk flow properties were evaluated, and a good prediction model was obtained by selecting five out of 14 bulk flow properties. The constructed model also predicted TWV well in the validation dataset. The applied approach is useful for constructing a simple model to better understand the phenomenon (die filling in this case), and the constructed model can be expanded further by including blends manufactured by dry or wet granulation.

Extracellular vesicles as a drug delivery system: A systematic review of preclinical studies.

During the past decades, extracellular vesicles (EVs) have emerged as an attractive drug delivery system. Here, we assess their pre-clinical applications, in the form of a systematic review. For each study published in the past decade, disease models, animal species, EV donor cell types, active pharmaceutical ingredients (APIs), EV surface modifications, API loading methods, EV size and charge, estimation of EV purity, presence of biodistribution studies and administration routes were quantitatively analyzed in a defined and reproducible way. We have interpreted the trends we observe over the past decade, to define the niches where to apply EVs for drug delivery in the future and to provide a basis for regulatory guidelines.

Development of low dose micro-tablets by high shear wet granulation process.

Low dose micro-tablets with acceptable quality attributes, specifically content uniformity (CU), would not only enhance the dose flexibility in the clinic, but also decrease excipient burden in pediatric population. Considering the CU challenges associated with directly compressed low dose micro-tablets, in this study, high shear wet granulation (HSWG) process was evaluated to manufacture micro-tablets with reduced CU variability. The impact of active pharmaceutical ingredient (API) particle size (D90 - 18-180µm) and loading (0.67-16.67% w/w) on the critical quality attributes of micro-tablets (1.2 and 1.5mm) like weight variability, CU, and dissolution were evaluated. Experimental results showed that final blends with flow function coefficient (ffc)≥5.4 or Hausner ratio (HR)≤1.43 facilitated robust compression of micro-tablets. With enhanced weight control, all the batches except the 1.2mm micro-tablets and 2.0mm micro-tablets with 0.67% w/w API loading and coarse API particle size (D90 - 180µm) resulted in CU variability that meets the USP <905> CU acceptance criteria for individual micro-tablets. Apart from the above mentioned 1.2mm micro-tablets, all the batches meet the USP <905> CU acceptance criteria for composites of 10 or more micro-tablets. Precise delivery of micro-tablets manufactured in the current study would allow dose titration in the increments of 11 mcg. The API particle size and loading impacted the in-vitro dissolution performance of micro-tablets with smaller API particle size and lower loading resulting in faster release profiles. This study provides a framework for developing low dose micro-tablets with acceptable quality attributes using HSWG process for micro-dosing, enhanced dose flexibility, and decreased excipient burden.

Drug amorphisation by fluid bed hot-melt impregnation of mesoporous silica carriers

• Solvent-free process for converting crystalline drug to amorphous form. • Successful co-fluidisation of ibuprofen and mesoporous silica particles. • No recrystallisation for drug loadings up to 50% wt. • Exceptional dissolution rate enhancement at both acidic and neutral pH. Amorphisation using mesoporous inorganic carriers represents an emerging formulation strategy for the dissolution rate enhancement of poorly water-soluble Active Pharmaceutical Ingredients (APIs). This approach employs API loading to a porous carrier, which stabilises the amorphous form and prevents recrystallisation due to spatial confinement in the mesopores. In this work, we utilise recently discovered silica particles with a unique pore structure that contain well-connected macropores for rapid capillary transport of the molten API, alongside mesopores for efficient drug amorphisation. We demonstrate that these particles enable efficient drug loading by a solvent-free process, namely hot-melt impregnation in a fluidised bed reactor. By controlling the process temperature and therefore the melt-in rate of the API, we show that the co-fluidisation of the API source crystals and silica carrier particles is possible without wall build-up or agglomeration. Using ibuprofen as a model API, we systematically investigate the effect of drug loading (30–50% w/w) and process conditions (heating time, process temperature) on the physico-chemical and dissolution properties of the product. The amorphous content of the silica particles after drug loading was established by DSC and XRPD and the chemical stability was confirmed by FTIR spectroscopy. More than a five-fold dissolution rate enhancement compared to crystalline API was achieved by fluid bed amorphisation.

Effect of solvent selection on drug loading and amorphisation in mesoporous silica particles

Increasing the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) is a key strategy used for improving their oral bioavailability. One of the formulation approaches is API loading to mesoporous carrier particles, which can increase the dissolution rate through the combination of improved powder wettability and dispersion, higher surface area, and API conversion from crystalline to the amorphous state. From the formulation process point of view, the maximum achievable drug loading is a crucial parameter, which depends on the loading method. Drug loading by sorption from a solution is a technologically attractive approach, since it involves familiar unit operations (mixing, filtration, drying). However, the success of the equilibrium sorption approach depends on the choice of the solvent. In this work we present an experimental study of loading efficiency to mesoporous silica particles, based on a set of 10 APIs combined with 6 different solvents at a range of concentrations. We show that due to the competitive nature of the adsorption process, the solvent with the highest API solubility is not necessarily the best candidate for maximising the API loading. Based on the investigated drug-solvent combinations, we show that the dielectric constant of the solvent is a good predictor of loading efficiency and can be used as a general guideline for solvent selection. On the other hand, we did not find any systematic correlation between commonly measured API properties such as logP and their loading efficiency.

Molecular-level insight into hot-melt loading and drug release from mesoporous silica carriers

Drug amorphisation by loading to inorganic mesoporous carriers represents an emerging area of improving the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). In this work, for the first time, a molecular-level insight into the process of API loading to mesoporous SiO2 (silica) carriers by the hot-melt impregnation method and its subsequent release during dissolution was obtained using ATR-FTIR spectroscopic imaging. A physical mixture of ibuprofen crystals and mesoporous silica particles was heated and the dynamics of melt loading into the silica pore structure was directly observed in situ by ATR-FTIR spectroscopic imaging. The loss of crystallinity, the redistribution of the API in the silica pore network and the subsequent stabilisation of the amorphous form upon cooling were proven. The API was involved in two different kinds of molecular-level interactions: API dimers in the amorphous bulk, and individual API molecules adsorbed on the silica surface. The melt-loaded silica carriers were comprehensively characterised by DSC, SEM and dissolution tests, which proved dissolution rate enhancement due to amorphisation of the API. Drug release form the hot-melt loaded mesoporous silica carriers was observed in real time and the conditions leading to local re-crystallisation of super-saturated solution of the API were identified.

A polymer-free, biomimicry drug self-delivery system fabricated via a synergistic combination of bottom-up and top-down approaches.

Compared to conventional carrier-assistant drug delivery systems (DDSs), drug self-delivery systems (DSDSs) have advantages of unprecedented drug loading capacity, minimized carrier-related toxicity and ease of preparation. However, the colloidal stability and blood circulation time of DSDSs still need to be improved. Here we report on the development of a novel biomimicry drug self-delivery system by the integration of a top-down cell membrane complexing technique into our self-delivery multifunctional nano-platform made from bottom-up approach that contains 100% active pharmaceutical ingredients (API) of Pheophorbide A and Irinotecan conjugates (named PI). Compared to conventional cell membrane coated nanoparticles with polymer framework as core and relatively low drug loading, this system consisting of red blood cell membrane vesicles complexed PI (RBC-PI) is polymer-free with up to 50% API loading. RBC-PI exhibited 10 times higher area under curve in pharmacokinetic study and much lower macrophage uptake compared with the parent PI nanoparticles. RBC-PI retained the excellent chemophototherapeutic effects of the PI nanoparticles, but possessed superior anti-cancer efficacy with prolonged blood circulation, improved tumor delivery, and enhanced photothermal effects in animal models. This system represents a novel example of using cell membrane complexing technique for effective surface modification of DSDSs. This is also an innovative study to form a polymer-free cell membrane nanoparticle complexing with positive surface charged materials. This biomimicry DSDS takes advantages of the best features from both systems to make up for each other's shortcomings and posed all the critical features for an ideal drug delivery system.

In-process rheometry as a PAT tool for hot melt extrusion

Real time measurement of melt rheology has been investigated as a Process Analytical Technology (PAT) to monitor hot melt extrusion of an Active Pharmaceutical Ingredient (API) in a polymer matrix. A developmental API was melt mixed with a commercial copolymer using a heated twin screw extruder at different API loadings and set temperatures. The extruder was equipped with an instrumented rheological slit die which incorporated three pressure transducers flush mounted to the die surface. Pressure drop measurements within the die at a range of extrusion throughputs were used to calculate rheological parameters, such as shear viscosity and exit pressure, related to shear and elastic melt flow properties, respectively. Results showed that the melt exhibited shear thinning behavior whereby viscosity decreased with increasing flow rate. Increase in drug loading and set extrusion temperature resulted in a reduction in melt viscosity. Shear viscosity and exit pressure measurements were found to be sensitive to API loading. These findings suggest that this technique could be used as a simple tool to measure material attributes in-line, to build better overall process understanding for hot melt extrusion.

The evaluation of physical properties of injection molded systems based on poly(ethylene oxide) (PEO)

The effect of product design parameters on the formation and properties of an injection molded solid dosage form consisting of poly(ethylene oxide)s (PEO) and two different active pharmaceutical ingredients (APIs) was studied. The product design parameters explored were melting temperature and the duration of melting, API loading degree and the molecular weight (Mw) of PEO. The solid form composition of the model APIs, theophylline and carbamazepine, was of specific interest, and its possible impact on the in vitro drug release behavior.Mw of PEO had the greatest impact on the release rate of both APIs. High Mw resulted in slower API release rate. Process temperature had two-fold effect with PEO 300,000g/mol. Firstly, higher process temperature transformed the crystalline part of the polymer into metastable folded form (more folded crystalline regions) and less into the more stable extended form (more extended crystalline regions), which lead to enhanced theophylline release rate. Secondly, the higher process temperature seemed to induce carbamazepine polymorphic transformation from p-monoclinic form III (carbamazepine (M)) into trigonal form II (carbamazepine (T)). The results indicated that the actual content of carbamazepine (T) affected drug release behavior more than the magnitude of transformation.

Manufacturing of a Secretoneurin Drug Delivery System with Self-Assembled Protamine Nanoparticles by Titration.

Since therapeutic peptides and oligonucleotides are gathering interests as active pharmaceutical ingredients (APIs), nanoparticulate drug delivery systems are becoming of great importance. Thereby, the possibility to design drug delivery systems according to the therapeutic needs of APIs enhances clinical implementation. Over the last years, the focus of our group was laid on protamine-oligonucleotide-nanoparticles (so called proticles), however, the possibility to modify the size, zeta potential or loading efficiencies was limited. Therefore, at the present study we integrated a stepwise addition of protamine (titration) into the formation process of proticles loaded with the angiogenic neuropeptide secretoneurin (SN). A particle size around 130 nm was determined when proticles were assembled by the commonly used protamine addition at once. Through application of the protamine titration process it was possible to modify and adjust the particle size between approx. 120 and 1200 nm (dependent on mass ratio) without influencing the SN loading capacity. Dynamic light scattering pointed out that the difference in particle size was most probably the result of a secondary aggregation. Initially-formed particles of early stages in the titration process aggregated towards bigger assemblies. Atomic-force-microscopy images also revealed differences in morphology along with different particle size. In contrast, the SN loading was only influenced by the applied mass ratio, where a slight saturation effect was observable. Up to 65% of deployed SN could be imbedded into the proticle matrix. An in-vivo biodistribution study (i.m.) showed a retarded distribution of SN from the site of injection after the application of a SN-proticle formulation. Further, it was demonstrated that SN loaded proticles can be successfully freeze-dried and resuspended afterwards. To conclude, the integration of the protamine titration process offers new possibilities for the formulation of proticles in order to address key parameters of drug delivery systems as size, API loading or modified drug release.

Molecular-Level Control of Ciclopirox Olamine Release from Poly(ethylene oxide)-Based Mucoadhesive Buccal Films: Exploration of Structure-Property Relationships with Solid-State NMR.

Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX-2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer-drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure-property relationships in these complex pharmaceutical solids.

A Novel Approach for Analyzing the Dissolution Mechanism of Solid Dispersions

To analyze the dissolution mechanism of solid dispersions of poorly water-soluble active pharmaceutical ingredients (APIs), to predict the dissolution profiles of the APIs and to find appropriate ways to improve their dissolution rate. The dissolution profiles of indomethacin and naproxen from solid dispersions in PVP K25 were measured in vitro using a rotating-disk system (USP II). A chemical-potential-gradient model combined with the thermodynamic model PC-SAFT was developed to investigate the dissolution mechanism of indomethacin and naproxen from their solid dispersions at different conditions and to predict the dissolution profiles of these APIs. The results show that the dissolution of the investigated solid dispersions is controlled by dissolution of both, API and PVP K25 as they codissolve according to the initial API loading. Moreover, the dissolution of indomethacin and naproxen was improved by decreasing the API loading in polymer (leading to amorphous solid dispersions) and increasing stirring speed, temperature and pH of the dissolution medium. The dissolution of indomethacin and naproxen from their amorphous solid dispersions is mainly controlled by the surface reaction, which implies that indomethacin and naproxen dissolution can be effectively improved by formulation design and by improving their solvation performance. The chemical-potential-gradient model combined with PC-SAFT can be used to analyze the dissolution mechanism of solid dispersions and to describe and predict the dissolution profiles of API as function of stirring speed, temperature and pH value of the medium. This work helps to find appropriate ways to improve the dissolution rate of poorly-soluble APIs.

NON-NEWTONIAN SUSPENSION FORMULATIONS FOR IMPROVED STABILITY AND DELIVERY OF AUTOINJECTABLE CBRN COUNTERMEASURES

Summary Autoinjectors are commonly employed by the United States and other countries to deliver emergency therapeutics to counteract the effects of various chemical agent threats, including nerve agents. Autoinjector combination products (autoinjector and drug product) used by the military can have drawbacks, including insufficient thermal stability of drug products, limited aqueous solution concentration of active pharmaceutical ingredients (APIs), and complicated and expensive designs for delivering multiple drugs simultaneously. We have developed a novel Enhanced Formulation (EF) technology that solves these problems, using nanoparticle suspensions in biocompatible cottonseed oil (CSO) instead of aqueous solutions of API. The hydrophobic CSO prevents hydrolytic degradation by limiting exposure to water, and the noninteraction of co-suspended particles simplifies multi-drug cocktail therapies. The high API loading (10% or more) gives the formulations non-Newtonian rheological behavior, with high zero-shear viscosity to resist sedimentation, and shear thinning to allow injection with standard autoinjectors and needles.

Formulation and manufacture of pharmaceuticals by fluidized‐bed impregnation of active pharmaceutical ingredients onto porous carriers

A manufacturing method is presented for solid dosage forms using fluidized‐bed impregnation, which could eliminate many of the challenges during solid dosage manufacturing. The main difference between impregnation and dry blending is the placement of the active pharmaceutical ingredient (API) inside a porous carrier. This makes the final material flow properties independent of the physical properties of the API. The method consists of spraying an API solution in appropriate solvent onto a carefully chosen porous excipient in a fluidized state. The solution penetrates the porous carrier due to capillary forces and the solvent is evaporated soon after that. Impregnation and drying occur simultaneously, which makes this impregnation method suitable for continuous implementation. Carefully choosing the operating conditions allows impregnation to occur without introducing spray drying or spray coating of the API. The method is shown to generate an impregnated excipient with very high degree of homogeneity independent of the API loading. It is also shown that mild milling further improves blend uniformity to RSD levels below 1%, which are challenging to achieve using conventional techniques. On impregnation, the final physical properties of the material are seen to be mainly unchanged from the initial excipient properties. A study of this one‐step manufacturing method is described, using acetaminophen as the model drug and anhydrous calcium phosphate dibasic as the porous excipient. The experimental work presented establishes a proof of concept and investigates in detail blend uniformity, physical state of impregnated API, final physical properties of impregnated material, compressibility during tableting, capsule filling, and release profile of the final capsule formulation. It also discusses potential ways for drug release control and improvements using impregnation. © 2013 American Institute of Chemical Engineers AIChE J, 59: 4538–4552, 2013