Water-soluble Active Pharmaceutical Ingredients Research Articles

Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers

The aim of this study was to investigate dermal delivery of the new active pharmaceutical ingredient (API) TOP-N53 into diabetic foot ulcer using an in vitro wound model consisting of pig ear dermis and elucidate the impact of drug formulation and wound dressing taking into consideration clinical relevance in the home care setting and possible bacterial infection. Different formulation approaches for the poorly water-soluble API including colloidal solubilization, drug micro-suspension and cosolvent addition were investigated; moreover, the effect of (micro-)viscosity of hydrogels used as primary wound dressing on delivery was assessed. Addition of Transcutol® P as cosolvent to water improved solubility and was significantly superior to all other approaches providing a sustained three-day delivery that reached therapeutic drug levels in the tissue. Solubilization in micelles or liposomes, on the contrary, did not boost delivery while micro-suspensions exhibited sedimentation on the tissue surface. Microbial contamination was responsible for considerable metabolism of the drug leading to tissue penetration of metabolites which may be relevant for therapeutic effect. Use of hydrogels under semi-occlusive conditions significantly reduced drug delivery in a viscosity-dependent fashion. Micro-rheologic analysis of the gels using diffusive wave spectroscopy confirmed the restricted diffusion of drug particles in the gel lattice which correlated with the obtained tissue delivery results. Hence, the advantages of hydrogel dressings from the applicatory characteristic point of view must be weighed against their adverse effect on drug delivery. The employed in vitro wound model was useful for the assessment of drug delivery and the development of a drug therapy concept for chronic diabetic foot ulcer. Mechanistic insights about formulation and dressing performance may be applied to drug delivery in other skin conditions such as digital ulcer.

The step-wise dissolution method: An efficient DSC-based protocol for verification of predicted API–polymer compatibility

The development of an amorphous solid dispersion (ASD) is a promising strategy for improving the low bioavailability of many poorly water-soluble active pharmaceutical ingredients (APIs). The construction of a temperature–composition (T–C) phase diagram for an API–polymer combination is imperative as it can provide critical information that is essential for formulating stable ASDs. However, the currently followed differential scanning calorimetry (DSC)-based strategies for API solubility determination in a polymer at elevated temperatures are inefficient and, on occasions, unreliable, which may lead to an inaccurate prediction at lower temperatures of interest (i.e., T = 25 °C). Recently, we proposed a novel DSC-based protocol called the “step-wise dissolution” (S-WD) method, which is both cost- and time-effective. The objective of this study was to test the applicability of the S-WD method regarding expeditious verification of the purely-predicted API–polymer compatibility via the perturbed chain-statistical associating fluid theory (PC-SAFT) equation of state (EOS). Fifteen API–polymer T–C phase diagrams were reliably constructed, with three distinct API–polymer case types being identified regarding the approach used for the S-WD method. Overall, the PC-SAFT EOS provided satisfactory qualitative descriptions of the API–polymer compatibility, but not necessarily accurate quantitative predictions of the API solubility in the polymer at T = 25 °C. The S-WD method was subsequently modified and an optimal protocol was proposed, which can significantly reduce the required experimental effort.

Impact of Additives on Drug Particles during Liquid Antisolvent Crystallization and Subsequent Freeze-Drying.

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200-300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, most-stable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process.

Biocatalytic Insights for The Synthesis of New Potential Prodrugs: Design of two Ibuprofen Derivatives

Due to its effectiveness, ibuprofen is one of the most popular anti-inflammatory drugs worldwide. However, the poor water solubility of this active ingredient severely limits its spectrum of pharmaceutical formulations (and often results in severe adverse effects due to high administered doses). To overcome these limitations, in this work, we enzymatically synthesized more hydrophilic derivatives of ibuprofen through its covalent attachment to two biobased polyalcohols: erythritol and glycerol. Herein, we report the optimized reaction conditions to produce an IBU–erythritol ester (82% ± 4% of conversion) by using Candida antarctica lipase B (CalB). Furthermore, we also report the enantioselective solventless esterification of (S)-ibuprofen with glycerol (83% ± 5% of conversion), exploiting immobilized Rhizomucor miehei lipase as a biocatalyst. The full NMR characterizations of the prodrug esters were performed via 1H, 13C-NMR, DEPT, COSY, HSQC, and HMBC-NMR. The approach reported in this work can be extended to a large variety of poorly water-soluble active pharmaceutical ingredients (APIs).

The shelf life of ASDs: 2. Predicting the shelf life at storage conditions

Amorphous solid dispersions (ASDs) are a widely used formulation technology for poorly water-soluble active pharmaceutical ingredients (API). Depending on the API-polymer combination and API load in the ASD, the amorphous API might be thermodynamically metastable and crystallize over time. The crystallization onset is one critical factor that can define the shelf life of the ASD. Thus, for ASD formulations, long-term stability against crystallization of the API is of particular interest. This work presents a method for predicting the long-term physical stability of ASDs (crystallization onset time). The new approach combines the Johnson-Mehl-Avrami-Kolmogorov (JMAK) equation with classical nucleation theory. The shelf life predicted using the new approach depends on supersaturation (determined with PC-SAFT), viscosity (determined with WLF equation or Arrhenius equation) and two specific model parameters k’ and B. The latter were fitted to a few fast crystallization-kinetics measurements above the glass transition of the ASD. An additional crystallization-kinetics measurement below the glass-transition temperature of the ASD was used to determine the Arrhenius parameters. Once all parameters are determined for a given API/polymer combination and manufacturing method, they are valid for any API load, temperature, and RH. The proposed approach allows predicting the shelf life (crystallization onset) of a potential ASD in early stage of development within a few days. It was successfully verified for ASDs stored at 25 °C and 10% RH or 60% RH.

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.

Can Pure Predictions of Activity Coefficients from PC-SAFT Assist Drug-Polymer Compatibility Screening?

The bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved via the formulation of an amorphous solid dispersion (ASD), where the API is incorporated into a suitable polymeric carrier. Optimal carriers that exhibit good compatibility (i.e., solubility and miscibility) with given APIs are typically identified through experimental means, which are routinely labor- and cost-inefficient. Therefore, the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state, a popular thermodynamic model in pharmaceutical applications, is examined in terms of its performance regarding the computational pure prediction of API-polymer compatibility based on activity coefficients (API fusion properties were taken from experiments) without any binary interaction parameters fitted to API-polymer experimental data (that is, kij = 0 in all cases). This kind of prediction does not need any experimental binary information and has been underreported in the literature so far, as the routine modeling strategy used in the majority of the existing PC-SAFT applications to ASDs comprised the use of nonzero kij values. The predictive performance of PC-SAFT was systematically and thoroughly evaluated against reliable experimental data for almost 40 API-polymer combinations. We also examined the effect of different sets of PC-SAFT parameters for APIs on compatibility predictions. Quantitatively, the total average error calculated over all systems was approximately 50% in the weight fraction solubility of APIs in polymers, regardless of the specific API parametrization. The magnitude of the error for individual systems was found to vary significantly from one system to another. Interestingly, the poorest results were obtained for systems with self-associating polymers such as poly(vinyl alcohol). Such polymers can form intramolecular hydrogen bonds, which are not accounted for in the PC-SAFT variant routinely applied to ASDs (i.e., that used in this work). However, the qualitative ranking of polymers with respect to their compatibility with a given API was reasonably predicted in many cases. It was also predicted correctly that some polymers always have better compatibility with the APIs than others. Finally, possible future routes to improve the cost-performance ratio of PC-SAFT in terms of parametrization are discussed.

Tailored ASD destabilization - Balancing shelf life stability and dissolution performance with hydroxypropyl cellulose

Amorphous solid dispersion (ASD) formulations are preferred enabling formulations for poorly water soluble active pharmaceutical ingredients (API) as they reliably enhance the dissolution behavior and solubility. Balancing a high stability against unwanted transformations such as crystallization and amorphous phase separation during storage on the one hand and optimizing the dissolution behavior of the formulation (high supersaturation and maintenance for long time) on the other hand are essential during formulation development. This study assessed the potential of ternary ASDs (one API and two polymers) containing the polymers hydroxypropyl cellulose together with poly(vinylpyrrolidone-co-vinyl acetate) (PVP VA64) or hydroxypropyl cellulose acetate succinate to stabilize the amorphously embedded APIs fenofibrate and simvastatin during storage and to enhance the dissolution performance. Thermodynamic predictions using the PC-SAFT model revealed for each combination of polymers the optimal polymer ratio, maximum API load that is thermodynamically stable as well as miscibility of the two polymers. The stability predictions were validated by three months enduring stability tests, followed by a characterization of the dissolution behavior. The thermodynamically most stable ASDs were found to be the ASDs with deteriorated dissolution performance. Within the investigated polymer combinations, physical stability and dissolution performance opposed each other.

Biopharmaceutical justification of the creation of self-emulsifying drug delivery systems with simvastatin

The aim of the research – to conduct biopharmaceutical tests of capsules with a self-emulsifying delivery system of simvastatin to confirm the effectiveness and feasibility of introducing into the composition of self-emulsifying drug delivery systems active pharmaceutical ingredients that are difficult to dissolve in the gastric juice environment.
 Material and methods. Substances, excipients, reagents and materials used during research were simvastatin (India, p. DK40-2005021, 99.09 %), castor oil (Ukraine), polyethylene glycol 40 hydrogenated castor oil (India), Tween 80 (Ukraine), glycerol monostearate (Gustav Heess GmbH, Germany), polyethylene glycol 100 stearate (ERCA, Italy), hard gelatin capsules No. 3 white (China), 0.1 M hydrochloric acid solution (made from concentrated hydrochloric acid), ethanol 96 % (Ukraine), filter paper 90 mm white tape (Ukraine). The reference drug is "Simvastatin-Sandoz" (Salyutas Pharma, Germany, series LX5161).
 An Evolution 60S spectrophotometer (USA) was used to carry out studies by absorption spectrophotometry.
 Results. Preliminary study of the absorption spectra of absorption of the substance, bases, gelatin capsules, developed self-emulsifying systems and the reference drug made it possible to predict and optimize the conduct of biopharmaceutical research. The study of the release of simvastatin from the developed delivery systems and the reference drug, which was carried out at a temperature of 37 ℃ in an environment of 0.1M hydrochloric acid, showed that the introduction of simvastatin into the composition of the investigated self-emulsifying compositions allows to increase its solubility in this solvent by five times, compared to the reference drug.
 Conclusions. The obtained results indicate the effectiveness of the introduction of simvastatin into the composition of self-emulsifying drug delivery systems and the feasibility of using such systems to improve the solubility and accelerate the release of a poorly water-soluble active pharmaceutical ingredient into the gastric juice environment

Influence of Poloxamer on the Dissolution and Stability of Hot-Melt Extrusion–Based Amorphous Solid Dispersions Using Design of Experiments

The current study aimed to see the effects of poloxamer P407 on the dissolution performance of hydroxypropyl methylcellulose acetate succinate (AquaSolve™ HPMC-AS HG)-based amorphous solid dispersions (ASD). A weakly acidic, poorly water-soluble active pharmaceutical ingredient (API), mefenamic acid (MA), was selected as a model drug. Thermal investigations, including thermogravimetry (TG) and differential scanning calorimetry (DSC), were conducted for raw materials and physical mixtures as a part of the pre-formulation studies and later to characterize the extruded filaments. The API was blended with the polymers using a twin shell V-blender for 10min and then extruded using an 11-mm twin-screw co-rotating extruder. Scanning electron microscopy (SEM) was used to study the morphology of the extruded filaments. Furthermore, Fourier-transform infrared spectroscopy (FT-IR) was performed to check the intermolecular interactions of the components. Finally, to assess the in vitro drug release of the ASDs, dissolution testing was conducted in phosphate buffer (0.1M, pH 7.4) and hydrochloric acid-potassium chloride (HCl-KCl) buffer (0.1M, pH 1.2). The DSC studies confirmed the formation of the ASDs, and the drug content of the extruded filaments was observed to be within an acceptable range. Furthermore, the study concluded that the formulations containing poloxamer P407 exhibited a significant increase in dissolution performance compared to the filaments with only HPMC-AS HG (at pH 7.4). In addition, the optimized formulation, F3, was stable for over 3months when exposed to accelerated stability studies.

A high throughput approach of selecting excipients for solubility enhancement of BCS Class II active pharmaceutical ingredients for oral dosage forms

Scientists have been faced with the challenge of selecting the right solubilizing excipients for solubility enhancement of poorly water-soluble active pharmaceutical ingredients for decades. In this investigation, the purpose was to ease some of those challenges by developing a first-intent matrix for selecting solubilizing excipients that may potentially be used in an oral solid dosage formulation. This was accomplished by generating 2304 data points using high throughput experimentation to assess the impact of eleven commonly used formulation excipients, at varying levels, on the solubility enhancement of a weak acid (Ibuprofen), weak base (Cinnarizine), and non-ionizable (Griseofulvin) drug substance over a time span from 1 h to equilibrium in simulated gastrointestinal fluids (SGF, FaSSIF, FeSSIF) and water. The results indicate that the enhancement of drug concentrations by use of solubilizing excipients (surfactants and stabilizers) in oral solid dosage forms depends on the type, the amount of excipient, and the pH of the media. The importance of this work is that formulation scientists now have a new addition to the formulation development toolkit for selecting the right solubilizing excipients and amounts suitable for solubility enhancement based on the class of active pharmaceutical ingredients. This first-intent solubilizer selection approach for the different drug classes simplifies the early development process to enable acceleration to candidate selection, formulation design, and product development for first-time-in-human studies.

Effect of different seed crystals on the supersaturation state of ritonavir tablets prepared by hot-melt extrusion

Hot-melt extrusion (HME) is a technology increasingly common for the commercial production of pharmaceutical amorphous solid dispersions (ASDs), especially for poorly water-soluble active pharmaceutical ingredients (APIs). However, recrystallization of the APIs during dissolution must be prevented to maintain the supersaturation state enabled by ASD. Unfortunately, the amorphous formulation may be contaminated by seed crystals during the HME manufacturing process, which could lead to undesirable crystal growth during the dissolution process. In this study, the dissolution behavior of ritonavir ASD tablets prepared using both Form I and Form II polymorphs was examined, and the effects of different seed crystals on crystal growth rates were investigated. The aim was to understand how the presence of seed crystals can impact the dissolution of ritonavir, and to determine the optimal polymorph and seeding conditions for the production of ASDs. The results showed that both Form I and Form II ritonavir tablets had similar dissolution profiles, which were also similar to the reference listed drug (RLD). However, it was observed that the presence of seed crystals, particularly the metastable Form I seed, led to more precipitation compared to the stable Form II seed in all formulations. The Form I crystals that precipitated from the supersaturated solution were easily dispersed in the solution and could serve as seeds to facilitate crystal growth. On the other hand, Form II crystals tended to grow more slowly and presented as aggregates. The addition of both Form I and Form II seeds could affect their precipitation behaviors, and the amount and form of the seeds had significant effects on the precipitation process of the RLD tablets, as are the tablets prepared with different polymorphs. In conclusion, the study highlights the importance of minimizing the contamination risk of seed crystals during the manufacturing process and selecting the appropriate polymorph for the production of ASDs.

Low-Dimensional Hollow Nanostructures: From Morphology Control to the Release of an Active Pharmaceutical Ingredient

The mechanism guiding the growth of hollow silica nanotubes or nanospheres was unveiled for the first time through in situ liquid-phase transmission electron microscopy, allowing visualization of the morphology of the hydrated species involved in the early stage of material formation. The combined action of a surfactant (F127) and a swelling agent (toluene) was essential for the development of targeted nanostructures, owing to the formation of surfactant-stabilized toluene droplets in the aqueous phase. The quantity of surfactant-stabilized toluene droplets was unambiguously pointed as the key parameter guiding the formation of either tubular or spherical nanostructures. Leveraging on the fundamental understanding of the parameters guiding the formation of hollow silica nanostructures, tubular and spherical carriers were prepared and exploited for the release of an active pharmaceutical ingredient (API). The impregnation of nanotubes and nanospheres with a poorly water-soluble API (curcumin) was investigated, leading to an optimal loading of 20 wt %. The accessibility of nanotubes and nanospheres showed to be highly beneficial to increase the release kinetics of the targeted API in simulated intestinal fluid, opening promising perspectives in the field. Release was more efficient than with other conventional mesoporous silica-based carriers.

The Effect of Surfactants and pH Modifying Agents on the Dissolution and Permeation of Pimobendan

Solubility and permeability are key parameters for establishing in vitro-in vivo correlation for poorly water-soluble active pharmaceutical ingredients (APIs). Recent studies demonstrate that not only solubility, but also effective permeability of the API may change due to the addition of solubilizing agents, and there is a certain mathematical relation between these physicochemical parameters. The aim of this study was to show the importance of early screening of solubility and permeability in presence of additives in order to achieve the expected bioavailability of the API. In this work, the effect of surfactants and microenvironmental pH modifiers were in focus, and pimobendan was chosen as model drug.In the case of pH modifiers, the equilibrium solubility of the API increased, while the permeability decreased significantly. No negative effect was observed for two surfactants at low additive levels, but these two additives also exhibited a slightly negative effect on permeability when used at higher concentrations. In the simultaneous dissolution-permeation studies the surfactants-containing formulation was found to have slightly higher flux than the pH-modifier-containing one. It can be due to the phenomenon that the dissolution of the active substance can be enhanced by these surfactants without any significant permeability reducing effect.The results obtained from the present study clearly demonstrate the importance of studying drug-additive interactions in every step of formulation development and based on these, the selection of the appropriate quality and quantity of additives. In addition, the results also underline the significance of performing simultaneous dissolution-permeation studies to predict bioavailability.

Embedding of Poorly Water-Soluble Drugs in Orodispersible Films-Comparison of Five Formulation Strategies.

The poor bioavailability of many newly developed active pharmaceutical ingredients (APIs) poses a major challenge in formulation development. To overcome this issue, strategies such as the preparation of amorphous solid dispersions (ASDs), and the application of the APIs in lipid nanocarriers or the wet-milling of the substances into nanoparticles have been introduced. In addition to an efficient formulation strategy, a dosage form that is accepted by all patients is also of great importance. To enable a simple application of the oral dosage form for all patients, orodispersible films (ODFs) are a very promising delivery platform for the APIs because the films directly disintegrate in the mouth. In this study, two poorly water-soluble APIs, fenofibrate and naproxen, were formulated using five different formulation strategies and then embedded in ODFs. It was found that the deliverable amount of API with one ODF highly depends on the formulation strategy as well as the physicochemical properties of the formulated API. The most promising film formulations were ASD-ODFs as well as films with API-loaded lipid nanoemulsions. Both showed a reduction of the dissolution time of the APIs from the ODF compared to an ODF with unformulated API micro particles. In addition, short disintegration times were achieved, although the mechanical film properties were slightly worse compared to the API-free film formulation.

High-throughput kinetic turbidity analysis for determination of amorphous solubility and excipient screening for amorphous solid dispersions

Many poorly water-soluble active pharmaceutical ingredients (APIs) rely on supersaturating formulations, such as amorphous solid dispersions (ASDs), to enhance oral bioavailability. ASDs kinetically trap amorphous solid drugs within polymer excipient matrices to maintain the amorphous drug states. The maximum solution concentration of the API in these formulations is known as the amorphous solubility. In early drug development with scarce material and time, high-throughput approaches to measuring amorphous solubility and screening excipient effects on crystallization risk offer significant benefits to preclinical formulation scientists. Here, we developed a high-throughput screening (HTS) workflow to quantify amorphous solubility and screen ASD excipients by automated kinetic turbidity analysis. Testing 20 model APIs with a wide range of biorelevant solubility, we demonstrated their apparent amorphous solubility determined by the HTS approach strongly correlated with quantification results using conventional liquid chromatography; while the real-time analysis significantly saved analytical time and experimental efforts. Furthermore, kinetic turbidity profiles elucidated distinct excipient effects on the precipitation process of APIs. These results were successfully translated to dissolution and precipitation behaviors of ASD formulations composed of the tested polymers. The high-throughput kinetic turbidity workflow presents a facile and information-rich approach for amorphous solubility screenings against excipients, and helps guide enabling formulation development.

Impact of spontaneous liposome modification with phospholipid polymer-lipid conjugates on protein interactions

ABSTRACT Liposome surface coating has been studied to avoid the immunological responses caused by the complement system, and alternative materials to poly(ethylene glycol) (PEG) have been explored recently since the production of anti-PEG IgM antibodies has been found in humans. We previously reported a liposome coating with poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC))-conjugated lipids (PMPC-lipids) and demonstrated its protective effect on blood protein interactions. Here, we attempted to modify the liposome surface by exogenously adding PMPC-lipids, which were spontaneously incorporated into the outer membrane via hydrophobic interactions. The polymerization degree of the PMPC segment was regulated from 10 to 100. The incorporated ratio of PMPC-lipid increased with a decrease in the degree of PMPC polymerization. Due to surface modification with PMPC-lipids, increase in the length of the PMPC-chain increased the size of the liposomes. The modified liposomes were kept stable for 14 d in terms of their size, polydispersity, and surface properties, where approximately 70% of PMPC-lipids were incorporated into the liposome surface. We demonstrated that liposome surface modification with PMPC-lipids can inhibit protein adsorption when exposed to serum, regardless of the degree of polymerization of PMPC. In addition, the PMPC-lipid modified surface was not recognized by the anti-PEG IgM antibody, whereas PEG-lipid was recognized by the antibody. Thus, we successfully fabricated an inert liposome surface via spontaneous modification with PMPC-lipids, where only the outer bilayer surface was modified. This technique can be available for full loading of water-soluble active pharmaceutical ingredient inside the modified liposome.

Processing of Lipid Nanodispersions into Solid Powders by Spray Drying.

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed into solid dosage forms, they could be administered orally, which is usually preferred by patients. Various solid lipids as well as oils were used in this study to prepare lipid nanodispersions, and it was shown that their nanoparticulate properties could be maintained when lactose in combination with SDS was used as matrix material in the spray-drying process. In addition, for lipid nanoemulsions loaded with fenofibrate, a good redispersibility with particle sizes below 300 nm at a lipid content of 26.8 wt.% in the powders was observed. More detailed investigations on the influence of the drying temperature yielded good results when the inlet temperature of the drying air was set at 110 °C or above, enabling the lactose to form an amorphous matrix around the embedded lipid particles. A tristearin suspension was developed as a probe to measure the temperature exposure of the lipid particles during the drying process. The results with this approach indicate that the actual temperature the particles were exposed to during the drying process could be higher than the outlet temperature.

The Shelf Life of ASDs: 1. Measuring the Crystallization Kinetics at Humid Conditions.

Amorphous solid dispersions (ASDs), where an active pharmaceutical ingredient (API) is dissolved in a polymer, are a favored formulation technique to achieve sufficient bioavailability of poorly water-soluble APIs. The shelf life of such ASDs is often limited by API crystallization. Crystallization depends strongly on the storage conditions (relative humidity and temperature) and the polymer selected for generating the ASD. Determining the crystallization kinetics of ASDs under various conditions requires suitable analytical methods. In this work, two different analytical methods were compared and cross-validated: The first builds on water-sorption measurements combined with thermodynamic predictions ( Eur. J. Pharm. Biopharm. 2018, 127, 183-193, DOI: 10.1016/j.toxrep.2018.11.002), whereas the second applies Raman spectroscopy. Using the two independent methods, factors influencing the crystallization kinetics of ASDs containing the API griseofulvin were investigated quantitatively. It was found that crystallization kinetics increases with increasing temperature and relative humidity. Additionally, the influence of different polymers (poly(vinylpyrrolidone-co-vinyl acetate) and Soluplus) on crystallization kinetics were investigated. The experimentally obtained crystallization kinetics were described using the Johnson-Mehl-Avrami-Kolmogorov model and are the basis for future shelf life predictions at desired storage conditions.

Formation of Ciprofloxacin–Isonicotinic Acid Cocrystal Using Mechanochemical Synthesis Routes—An Investigation into Critical Process Parameters

The mechanochemical synthesis of cocrystals has been introduced as a promising approach of formulating poorly water-soluble active pharmaceutical ingredients (APIs). In this study, hot-melt extrusion (HME) as a continuous process and grinding and ball milling as batch processes were employed to explore the feasibility of cocrystallization. Ciprofloxacin (CIP) and isonicotinic acid (INCA) were selected as the model API and coformer. CIP–INCA cocrystal was produced in all techniques. It was revealed that higher cocrystal content could be achieved at longer durations of grinding and ball milling. However, milling for more than 10 min led to increased co-amorphous content instead of cocrystal. A design of experiment (DoE) approach was used for deciphering the complex correlation of screw configuration, screw speed, and temperature as HME process parameters and their respective effect on final relative cocrystal yield. Statistical analysis showed that screw configuration, temperature, and their interaction were the most critical factors affecting cocrystallization. Interestingly, screw speed had minimal impact on the relative cocrystallization yield. Cocrystallization led to increased dissolution rate of CIP in phosphate buffer up to 2.5-fold. Overall, this study shed a light on the potential of mechanochemical synthesis techniques with special focus on HME as a continuous process for producing cocrystals.