Soluble Active Pharmaceutical Ingredients Research Articles

Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions.

The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinylpyrrolidone) (PVP K25) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH), and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847-2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64.

Regenerated cellulose capsules for controlled drug delivery: Part IV. In-vitro evaluation of novel self-pore forming regenerated cellulose capsules

In the present work, the release mechanisms of active pharmaceutical ingredients (APIs) enclosed in self-pore forming regenerated cellulose (RC) two-piece hard shell capsules are described. The RC capsules were fabricated using a modified dip-coating approach, which yielded an assembled dosage form that was equivalent in size and shape to a conventional gelatin two-piece hard shell capsule. Drug release characteristics from RC capsules were evaluated using potassium chloride, diphenhydramine hydrochloride, tramadol hydrochloride, niacinamide, acetaminophen and ketoprofen as model APIs. The RC capsules act as a barrier coated reservoir device that releases the enclosed API at a zero order release rate. When comparing all the API's release behavior from RC capsules, a power-law relationship was observed between their zero-order release rates and their respective aqueous solubilities. Osmotic as well as diffusive mechanisms are involved in the release of the enclosed API. The osmotic mechanism's contribution to zero order release rate increases as the aqueous solubility of the tested APIs inside the capsule increases. The osmotic mediated flux and the apparent diffusivity of the APIs through the capsule wall is a competitive process and the osmotic mediated flux of the enclosed API begins to override its diffusivity through the capsule wall as the API solubility increases. This behavior is attributed to the wide range of pore sizes observed in RC membranes, from our prior analysis. The fluid permeability analysis shows that the RC capsules presented in this work may be better suited for osmotic drug delivery applications than conventional encapsulated systems described in the literature.

Analysis of spironolactone polymorphs in active pharmaceutical ingredients and their effect on tablet dissolution profiles

Spironolactone (SPR) is a steroidal drug administered as a potassium-sparing diuretic for high blood pressure treatment. The drug shows incomplete gastrointestinal absorption due to its poor aqueous solubility. The physicochemical properties of SPR in crystal forms I and II suggest that differences in their aqueous solubility may lead to a lack of bioequivalence between solid-state formulations. In this study, SPR polymorphs in five batches of active pharmaceutical ingredients (APIs) from three manufacturers were characterized using powder X-ray diffraction, infrared spectroscopy, thermal analysis, and solubility measurements. SPR tablets (50 mg) were manufactured in our laboratory using API in pure form II, and API in form II contaminated with form I, which was found in a commercial batch. Physicochemical quality evaluations of the manufactured tablets, along with five SPR tablets marketed in Brazil, were performed, and results indicated differences in their dissolution profiles. In the manufactured tablets, differences were associated with the increased solubility of API in form II contaminated with form I compared to API in pure form II. In the marketed SPR tablets, the formulation composition demonstrated an important role in the dissolution rate of the drug, leading to lack of pharmaceutical equivalence among the drug products.

ChemInform Abstract: Characterization and Quality Control of Pharmaceutical Cocrystals

AbstractReview: 106 refs.

Development of a novel physico-chemically and microbiologically stable oral solution of flecainide for pediatrics

There is as yet no commercialized preparation for oral administration of flecainide acetate (FA) to children. In such cases, manipulation of commercial tablets is the usual practice in pharmacy services of hospitals and compounding pharmacies, to provide a suitable dosage form for this vulnerable pediatric population group. In this study, we have formulated FA as an oral solution, as an alternative to the suspension elaborated from commercial tablets. Due to this sensitivity of young patients, we have used the pure active pharmaceutical ingredient (API) and the lowest permitted levels of pediatric excipients. Despite being a highly soluble API, only one of the formulations appears as a transparent solution due to complete FA solubilization. The proposed formulation is physico-chemically and microbiologically stable and the mass and dose uniformity is appropriate for 30 days’ storage at 25 °C.

Double Salt Ionic Liquids Containing the Trihexyl(tetradecyl)phosphonium Cation: The Ability to Tune the Solubility of Aromatics, Ethers, and Lipophilic Compounds

Ionic liquids (ILs) certainly have some interesting properties and this has led to tremendous growth in interest, knowledge, and applications of these materials in a diverse array of science and technology. However, the field is still dominated by study of the simplest binary salts and an over reliance on ‘magic’ solvent properties which currently limits their creative use for new technologies. Lately, the scientific community has been attracted towards “IL/IL mixtures” prepared by mixing two or more ILs, and (as was the case with the early studies of the binary salts), a focus on specific physicochemical properties. Interestingly, crystalline salts dissolved in ILs are seen as a different class of liquids (e.g., high ionicity ILs). We have found that the physical, chemical, and biological (i.e., the materials) properties of IL/IL mixtures (or Double Salt Ionic Liquids, DSILs, as we like to call them) seem to be mainly controlled by the intrinsic ion interactions which are influenced by the exact ion composition. Perhaps, a new way of thinking about these multi-ion fluids is needed in order to direct research toward an understanding of the complex and varied types of interionic forces possible in a liquid. We have proposed the DSIL concept to help guide our work towards obtaining this deeper understanding. In this nomenclature, any homogeneous liquid containing three or more ions (no matter how they are prepared) are described as DSILs and are defined by the specific ion combinations present. In this presentation, these concepts will be illustrated by discussion of the chemical, physical, and biological properties of several DSIL systems chosen to explore different interactions between the ions (i.e., Coulombic, hydrogen bonding, dispersion, etc.). While we will present physical properties as a function of composition, we will focus more on chemical properties illustrated by the solubilities of pharmaceuticals and on biological properties illustrated by changes in membrane transport, both as a function of ion composition. Spectroscopic studies will be presented to provide insight into specific ion-ion interactions. For example, the solubility of active pharmaceutical ingredients with different acidity and lipophilicity are finely tunable by varying the ratio of the ions (Figure 1). Such studies support the concept that each DSIL is a unique ionic fluid that is able to provide tunable property sets derived from the ions present and that these properties can be controlled by choosing the nature and the abundance of the ions. Figure 1

Continuous reactive crystallization of pharmaceuticals using impinging jet mixers

For reactive crystallization of pharmaceuticals that show a rapid reaction rate, low solubility of active pharmaceutical ingredient and hence a large supersaturation, it was found in a recent study that a process design which integrates an impinging jet mixer and batch stirred tank produces high quality crystals. The current investigation examines if the short processing time of reactive crystallization permits the impinging jet mixer—stirred tank design to be modified to operate in a continuous mode. The new design combines an impinging jet mixer for feed introduction and reaction with a continuous stirred tank reactor (CSTR) and tubular reactor for crystal growth. A study of reactive crystallization of sodium cefuroxime (an antibiotic), using first a 1L CSTR then scaling to a 50L CSTR, found that the new design produces crystals of higher crystallinity, narrower particle size, and improved product stability, than batch crystallizers. © 2016 American Institute of Chemical Engineers AIChE J, 63: 967–974, 2017

Micro-scale prediction method for API-solubility in polymeric matrices and process model for forming amorphous solid dispersion by hot-melt extrusion

A new predictive micro-scale solubility and process model for amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is presented. It is based on DSC measurements consisting of an annealing step and a subsequent analysis of the glass transition temperature (Tg). The application of a complex mathematical model (BCKV-equation) to describe the dependency of Tg on the active pharmaceutical ingredient (API)/polymer ratio, enables the prediction of API solubility at ambient conditions (25°C). Furthermore, estimation of the minimal processing temperature for forming ASDs during HME trials could be defined and was additionally confirmed by X-ray powder diffraction data. The suitability of the DSC method was confirmed with melt rheological trials (small amplitude oscillatory system). As an example, ball milled physical mixtures of dipyridamole, indomethacin, itraconazole and nifedipine in poly(vinylpyrrolidone-co-vinylacetate) (copovidone) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used.

Influence of Coformer Stoichiometric Ratio on Pharmaceutical Cocrystal Dissolution: Three Cocrystals of Carbamazepine/4-Aminobenzoic Acid.

Cocrystallization is a technique to optimize solid forms that shows great potential to improve the solubility of active pharmaceutical ingredients (APIs). In some systems, an API can form cocrystals in multiple stoichiometries with the same coformer. However, it remains unclear how coformer stoichiometry influences solubility. This paper investigates the pharmaceutical:coformer pair carbamazepine (CBZ)/p-aminobenzoic acid (PABA); both CBZ/PABA 1:1 and 2:1 cocrystals are known, and a novel 4:1 CBZ/PABA cocrystal is reported here. The 4:1 cocrystal is structurally characterized, and phase stability data suggest that it is a thermodynamically unstable form. Dissolution experiments show that there is no correlation between the cocrystal stoichiometry and dissolution rate in this system. On the other hand, with the relatively weak intermolecular interactions, metastable forms can be beneficial to dissolution rate, which suggests that more effort should be devoted to cocrystal production with kinetic growth methods.

Ibuprofen-Amino Acids Co-Crystal Screening Via Co-Grinding Methods

The importance of pharmaceutical co-crystals now has been recognized in order to improve the research and development in pharmaceutical industries. Low solubility of active pharmaceutical ingredient (API) has led to the growth of new pharmaceutical co-crystals formation as it enhances the physicochemical properties of the API. In this works, preparation of new co-crystal formation between ibuprofen (IBP) with selected amino acid compounds were performed by using dry grinding and liquid assisted grinding (LAG) techniques. Ibuprofen (IBP) was selected as the API meanwhile glycine (GLY), L-alanine (ALA) and L-proline (PRO) were selected as co-crystal former (CCF) agents. The products of IBP-co-former from grinding experiments for the formation of co-crystals were characterized and verified using X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC) and Fourier Transform Infra-Red Spectroscopy (FTIR). The finding reveals that the IBP-PRO co-crystals have successfully formed. For IBP-PRO system, new crystalline peaks from XRPD were recorded at 2θ values of 4.374°, 5.436° and 10.944° from dry grinding technique and 4.41°, 5.436° and 10.962° for liquid assisted grinding (LAG) technique. A new melting point of 257.49 °C was discovered for IBP-ALA indicates the possibility of co-crystals formation. On the other hand, the analysis for IBP-GLY shows that no co-crystals formed in the system.

Characterization and Quality Control of Pharmaceutical Cocrystals.

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

Solubility Measurement and Simulation of Rivaroxaban (Form I) in Solvent Mixtures from 273.15 to 323.15 K

The solubility of active pharmaceutical ingredients in various solvents is crucial to their industrial production and the development to final formulations. In this work, the solubility of rivaroxaban (form I) in the binary solvent mixtures of 1-methyl-2-pyrrolidinone with water, methanol, ethanol, and isopropanol from 273.15 to 323.15 K has been experimentally measured. Meanwhile, the dependence of the measured solubility on the temperature as well as on the composition of solvent mixtures has been simulated by Jouyban-Acree (JA) and nonrandom two liquid (NRTL) equations, respectively. The results show that as to the solubility simulation of the studied system JA and NRTL give average relative deviations of 0.1081 and 0.1064, respectively, suggesting that both JA and NRTL can act as an efficient simulation tool for the solubility of rivaroxaban (form I) in pure and mixture solvents at various temperatures.

Understanding Critical Quality Attributes for Nanocrystals from Preparation to Delivery.

Poor solubility of active pharmaceutical ingredients (APIs) is a great challenge for the pharmaceutical industry and, hence, drug nanocrystals are widely studied as one solution to overcome these solubility problems. Drug nanocrystals have comparatively simple structures which make them attractive for the formulation for poorly soluble drugs, and their capability to improve the dissolution in vitro is easily demonstrated, but turning the in vitro superior properties of nanocrystals to success in vivo, is often demanding: controlled (including enhanced) drug dissolution followed by successful permeation is not guaranteed, if for example, the dissolved drug precipitates before it is absorbed. In this review critical quality attributes related to nanocrystal formulations from production to final product performance in vivo are considered. Many important parameters exist, but here physical stability (aggregation tendency and solid state form), solubility properties influencing dissolution and supersaturation, excipient use to promote the maintenance of supersaturation, and finally the fate of nanocrystals in vivo are the main subjects of our focus.

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1).

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

High-Throughput Raman Spectroscopy Screening of Excipients for the Stabilization of Amorphous Drugs.

Low aqueous solubility of active pharmaceutical ingredients (APIs) is an enduring problem in pharmaceutical development, and it is becoming increasingly prevalent among new drug candidates. It is estimated that about 40% of drugs in the development pipeline and approximately 60% of the drugs coming directly from discovery suffer from poor aqueous solubility and slow dissolution, thereby reducing their bioavailability and efficacy and thus preventing their commercialization. It is well known that utilizing the amorphous form of a drug can be a useful approach to improve the dissolution rate and solubility of poorly water-soluble APIs. Amorphous compounds are thermodynamically unstable, but they can be stabilized by combining them with a carrier polymer (excipient) to form a solid dispersion. High-throughput Raman spectroscopy was used in this study to identify excipients that promote formation and stabilization of the amorphous drug form in solid dispersions. Four model APIs were used as poorly soluble drug candidates: ketoprofen, danazol, griseofulvin, and probucol. The Raman signals of excipients were generally negligible, and therefore Raman bands from the drugs were used with minimal spectral pre-processing. By comparing Raman spectra collected from the APIs in the crystalline and molten state, appropriate spectral features and regions were identified for the development of semi-quantitative methods to determine the amorphous content for each API. It is demonstrated that methods based on peak intensity ratio, peak width, peak distance, and classical least squares can all be effective methods for the screening of excipients. Interesting excipient-dependent phase transformation behavior was also observed for probucol.

Salt-kneading: alternative sizing of active pharmaceutical ingredients?

The most of currently produced active pharmaceutical ingredients (APIs) are poorly soluble in the human body. One of the options how to increase their dissolution rate is reducing their particle size. If very small particles of API are desired, traditional milling methods often cause smeared, agglomerated or non-flowing particles due to the forces applied. We tried to compare some of milling methods with the salt-kneading method, which is not typically used in the pharmaceutical industry. Salt-kneading process is driven by several variable parameters (e.g. the amount, hardness and particle size of the salt-kneading material), which influence the degree of size reduction of API particles which are chafed by a surplus of salt-kneading material. A model poorly-soluble API was separately processed with oscillation mill, vibratory mill and kneader; and the morphology, size distribution and solid form of prepared particles were analyzed. Our basic variation of salt-kneading parameters showed the potential of the salt-kneading method, which appears a very effective method of API controlled reduction. The final size can be modified according to the amount and properties of the salt-kneading material. The availability of such a method equips pharmaceutical scientists with a size-reduction method that provides very small, rounded and free-flowing particles of the poorly soluble API and reduces non-preferred needle shape.

Determination and prediction of solubilities of active pharmaceutical ingredients in selected organic solvents

The aim of this work was to measure the solubilities of active pharmaceutical ingredients (APIs) in various organic solvents using the synthetic-visual method. Two non-steroidal anti-inflammatory drugs, i.e., acetylsalicylic acid and acetaminophen, and two histamine H2 receptor antagonists, i.e., cimetidine and famotidine, were selected as the APIs. The solubilities of these APIs in different organic solvents, namely methanol, ethanol, 2-propanol, 1-octanol, and poly(ethylene glycol) 400, were determined in the temperature range of 260–360K. Cimetidine and famotidine, which have several polymorphs, were characterized using powder X-ray diffraction, scanning electron microscopy, and differential scanning calorimetry before the solubility measurements. The experimental results for the APIs except famotidine show that the solubilities at a given temperature decreased with increasing carbon number of the alcohol. The solubility data were represented by two activity coefficient models: NRTL and UNIQUAC. In addition, predictions of the solubilities using the group contribution models Pharma Modified UNIFAC and modified UNIFAC (Dortmund) were also performed. The predictions obtained using Pharma Modified UNIFAC were better than those obtained using modified UNIFAC (Dortmund).

Population data analysis of dissolution time profiles: Assessment of physicochemical properties of the drug, drug particles and the pharmaceutical formulation

Disintegration of finished dosage forms (FDF) and drug dissolution are fundamentally important processes that affect bioavailability. Established theories do not account for disintegration and usually assume sink conditions for drug dissolution that often do not apply. We present the theory to describe the disintegration of FDF with subsequent dissolution of liberated particles containing the active pharmaceutical ingredient (API) and its application using population data analysis. Population modeling, using dissolution profiles of 400mg cefditoren pivoxil tablets manufactured under various tableting pressures, characterized the intrinsic lifetime distribution of the particles and identified the presence of crystalline API in the formulation that was proven by X-ray diffraction. Modeling further estimated the disintegration time of FDF, the solubility of the amorphous API and its chemical instability in the medium that were in agreement with the experimentally determined values. This novel approach provides a quantitative understanding of the manufacturing process of FDF and can substantially contribute to the targeted development of finished dosage forms.

Development of orodispersible polymer films containing poorly water soluble active pharmaceutical ingredients with focus on different drug loadings and storage stability

The aim of this work was the development of orodispersible films containing different film forming polymers with focus on different drug loadings of two poorly water soluble APIs. Furthermore, physical stability of films was examined at two different storage conditions.Loperamide hydrochloride (LPH) and ibuprofen (IBU) were used as model drugs. Hydroxypropyl methylcellulose (HPMC) and three different types of hydroxypropyl cellulose (HPC) were used as film forming polymers. Suspensions were characterized with respect to their viscosity and particle sedimentation and films regarding their content uniformity, thickness, mass and stability. Principal component analysis (PCA) was used to evaluate the correlation between the wet film thickness, dry film thickness, mass of the films, API fraction in the suspension and the viscosity of the suspensions.The viscosity of the suspensions was dependent on the drug load and the polymer fraction but less so on the type of the utilized polymer. A correlation between the wet film thickness, the solid fraction and the mass of the films was established with an increase in mass by increasing the wet film thickness or the solid fraction. Films containing 50mgIBU/6cm2 film led to acceptable films. Storage experiments did not lead to an AV below 15 in all cases after storage for three and six months, attributed to the storage conditions and the quality of the films. Nevertheless, the development and production of flexible and homogeneous films of LPH and IBU was successfully achieved.

Predicting the Solubility Advantage of Amorphous Pharmaceuticals: A Novel Thermodynamic Approach.

For the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) to be improved, the transformation of crystalline APIs to the amorphous state has often been shown to be advantageous. As it is often difficult to measure the solubility of amorphous APIs, the application of thermodynamic models is the method of choice for determining the solubility advantage. In this work, the temperature-dependent solubility advantage of an amorphous API versus its crystalline form was predicted for five poorly soluble APIs in water (glibenclamide, griseofulvin, hydrochlorothiazide, indomethacin, and itraconazole) based on modeling the API/solvent phase diagrams using the perturbed-chain statistical associating fluid theory (PC-SAFT). Evaluation of the performance of this approach was performed by comparing the predicted solubility advantage to experimental data and to the solubility advantage calculated by the commonly applied Gibbs-energy-difference method. For all of the systems considered, PC-SAFT predictions of the solubility advantage are significantly more accurate than the results obtained from the Gibbs-energy-difference method.