Stability Of Active Pharmaceutical Ingredients Research Articles

Thermal Stability Kinetics and Shelf Life Estimation of the Redox-Active Therapeutic and Mimic of Superoxide Dismutase Enzyme, Mn(III) meso-Tetrakis(N-ethylpyridinium-2-yl)porphyrin Chloride (MnTE-2-PyPCl5, BMX-010).

Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl5, BMX-010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox-active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE-2-PyPCl5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn-porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N-dealkylation reaction. The thermal stability kinetics of the N-dealkylation process leading to MnTE-2-PyPCl5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid-state kinetic models and showed that MnTE-2-PyPCl5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol–1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition (t90%) of MnTE-2-PyPCl5 at 25°C was approximately 17 years, which is consistent with the high solid-state stability of the compound. These results represent the first study on the solid-state decomposition kinetics of Mn(III) 2-N-alkylpyridylporphyrins, contributing to the development of this class of redox-active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.

Lipid Nanoparticles as a Skin Wound Healing Drug Delivery System: Discoveries and Advances.

Chronic wounds are a remarkable cause of morbidity, requiring long-time treatments with a significant impact on the quality of life and high costs for public health. Although there are a variety of topical skin preparations commercially available, they have several limitations that frequently impair wound healing, such as drug instability, toxicity, limited time of action and ineffective skin permeation. In recent years, researchers have focused on the development of new effective treatments for wound healing and shown frequent interest in nanometric drug delivery systems to overcome such obstacles. In dermatology, lipid nanoparticles (LNPs) have received great attention from researchers due to their great functionalities, greater adhesion to the skin and film formation, enabling the hydration and maintenance of skin integrity, as well as present a more effective penetration through the skin barrier. This review provides an update on topical formulations based on Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) as wound healing treatments. Both SLNs and NLCs are able to increase solubility and stability of active pharmaceutical ingredients and increase skin penetration compared to the free drugs. Additionally, SLNs and NLCs can increase pharmacological activity, increase the release profile of the drugs, promote synergistic effects and improve the sensory properties of the final formulation. Topical dosage forms containing nanoparticles have been extensively evaluated for wound healing activity, mainly the dressings, films and scaffolds. Therefore, lipid nanoparticles have contributed in improving wound healing therapies when incorporated into other dosage forms with better efficacy and lesser adverse effects than conventional formulations.

Development of a dissolution method for lumefantrine and artemether in immediate release fixed dose artemether/lumefantrine tablets

BackgroundDissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets.MethodsThe dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products.ResultsA suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2 = 0.999) over the concentration range of 6.25–100 μg/ml. The results for precision were within the acceptance limit (%RSD < 2). The percent relative standard deviation (< 2%) and statistically non-significant (p > 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ± 0.2 or agitation speed = 100 ± 2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality.ConclusionsThe developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics.

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-β-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution.

Lipid Nanoparticle Topical and Transdermal Delivery: A Review on Production, Penetration Mechanism to Skin

Nanoparticulate drug delivery systems have an advanced and modern approach over the traditional delivery system. This systematic review on nanoparticulate drug delivery containing lipid and focus on preparation, challenges and advancement of delivery of the drug via topical and transdermal route. The first era of lipid nanoparticles were SLN and have more sustaining action as well as suitable for the higher permeation of drug. The NLC is the second generation lipid nanoparticles developed to overcome the limitation associated with SLN i.e low drug loading capacity, polymorphism of solid lipid. Production of solid lipid nanoparticles and nanostructured lipid carriers are produced by a variety of technologies which explored in the current review. Lipid nanoparticle has various properties for topical use of cosmetics and other pharmaceutical formulation, i.e. controlled and sustained release of medicaments, Physical and chemical stability of active pharmaceutical ingredients, targeted release, film formation and enhancing penetration with the enhancement of skin hydration. Skin hydration plays a major role in the topical delivery of API as it hydrates the skin which leads to opening of pores of skin. Due to occlusion nature of lipid nanoparticles trans epidermal water loss decline which softening the skin. The use of biodegradable grade lipid makes it more suitable because it does not cause any toxicity as created by polymeric nanoformulations. Furthermore, a discussion about the benefit/risk ratio of a nanoparticulate system containing lipids also explored in this paper. The SLN and NLC are a “nanosafe” carrier for the delivery of active pharmaceutical via topical route.

Chemometrics Approaches in Forced Degradation Studies of Pharmaceutical Drugs.

Chemometrics is the chemistry field responsible for planning and extracting the maximum of information of experiments from chemical data using mathematical tools (linear algebra, statistics, and so on). Active pharmaceutical ingredients (APIs) can form impurities when exposed to excipients or environmental variables such as light, high temperatures, acidic or basic conditions, humidity, and oxidative environment. By considering that these impurities can affect the safety and efficacy of the drug product, it is necessary to know how these impurities are yielded and to establish the pathway of their formation. In this context, forced degradation studies of pharmaceutical drugs have been used for the characterization of physicochemical stability of APIs. These studies are also essential in the validation of analytical methodologies, in order to prove the selectivity of methods for the API and its impurities and to create strategies to avoid the formation of degradation products. This review aims to demonstrate how forced degradation studies have been actually performed and the applications of chemometric tools in related studies. Some papers are going to be discussed to exemplify the chemometric applications in forced degradation studies.

Ionic liquid-based transdermal delivery of propranolol: a patent evaluation of US2018/0169033A1.

Ionic liquids (ILs) are organic salts of asymmetric organic cations and inorganic/organic anions and are considered green alternative to organic solvents. ILs have high thermal stability, low volatility, low toxicity and high biodegradability. ILs are frequently used for enhancing the solubility and stability of active pharmaceutical ingredients. This study describes an invention related to the preparation of amorphous melts of propranolol incorporated into transdermal patches for infantile hemangioma intervention. Reduction in skin irritation and a significant increase in transdermal permeability of propranolol from its amorphous melts was reported. However, toxicity and stability issues of the IL-based active pharmaceutical ingredients and their drug delivery systems are yet to be established from regulatory perspective before exploiting commercial viability of these forms.

Lipid nanoparticle topical &amp; transdermal delivery: a review on production, penetration mechanism to skin

Lipid nanoparticles are an alternative and modern carrier system to traditional drug delivery system i.e. liposomes and emulsions. This systematic review on lipid nanoparticles focus on production, challenges and advancement of delivery of drug via topical and transdermal route. Production of solid lipid nanoparticles and naostructured lipd carrier are produced by a variety of technique which explored in current review. Lipid nanoparticle exhibit many features for topical application of cosmetics and pharmaceutics, i.e. controlled release of actives, Physical and chemical stability of active pharmaceutical ingredients, drug targeting, occlusion, film formation and associated with it penetration enhancement and increase of skin hydration. Due to the production of lipid nanoparticles from physiological and/or biodegradable lipids, this carrier system exhibits an excellent tolerability. Furthermore an overview of the benefit/risk ratio of lipid nanoparticles also explored in this paper. The SLN &amp; NLC are a “nanosafe” carrier for the delivery of active pharmaceutical via topical route.

Toward Developing a Predictive Approach To Assess Electron Beam Instability during Transmission Electron Microscopy of Drug Molecules

During drug development control of polymorphism, particle properties and impurities are critical for ensuring a good quality, reproducible, and safe medicine. A wide variety of analytical techniques are employed in demonstrating the regulators control over the drug substance and product manufacturing, storage, and supply. Transmission electron microscopy (TEM) offers the opportunity to analyze in detail pharmaceutical systems at a length scale and limit of detection not readily achieved by many traditional techniques. However, the use of TEM as a characterization tool for drug development is uncommon due to possible damage caused by the electron beam. This work outlines the development of a model, using molecular descriptors, to predict the electron beam stability of active pharmaceutical ingredients (API). For a given set of conditions and a particular imaging or analytical mode, the total number of electrons per unit area, which causes observable damage to a sample in the TEM, can be defined as the critical fluence ( CF). Here the CF of 20 poorly water-soluble APIs were measured using selected area electron diffraction. Principal component analysis was used to select the most influential molecular descriptors on CF, which were shown to be descriptors involving the degree of conjugation, the number of hydrogen bond donors and acceptors, and the number of rotatable bonds. These were used to generate several multiple linear regression models. The model that provided the best fit to the measured CF data included the ratio of the number of conjugated carbons to nonconjugated carbons, the ratio of the number of hydrogen bond donors to acceptors, and the ratio of the number of hydrogen bond acceptors to donors. Using this model, the CF of the majority of the compounds was predicted within ±2 e-/Å2. Molecules with no hydrogen bond acceptors did not fit the model accurately possibly due to the limited sample size or the influence of other parameters not included in this model, such as intermolecular bond energies. The model presented can be used to support pharmaceutical development by quickly assessing the stability of other poorly soluble drugs in TEM. Provided that the model suggests that the API is relatively stable to electron irradiation, TEM offers the prospect of determining the presence of crystalline material at low levels at length scales and limits of detection unobtainable by other techniques. This is particularly so for amorphous solid dispersions.

Entacapone: Improving Aqueous Solubility, Diffusion Permeability, and Cocrystal Stability with Theophylline

Cocrystallization is a well-established technique to improve the solubility, bioavailability, and stability of active pharmaceutical ingredients (APIs) but permeability and diffusion rate control via cocrystals is relatively less well studied, and the exact role of coformers in influencing the diffusion rate of drug cocrystals is still not fully understood. The aqueous solubility and permeability diffusion of Entacapone, ETP, a Biopharmaceutical Classification System (BCS) Class IV drug of low solubility and low permeability, with Generally Regarded as Safe (GRAS) coformers has been studied. Fixed stoichiometry cocrystals of ETP with acetamide (ACT, 1:1), nicotinamide (NAM, 1:1), isonicotinamide (INAM, 1:1), pyrazinamide (PYZ, 1:1), and isoniazid (INZ), 1:1) were prepared by solvent-assisted grinding. Theophylline (THP) resulted in a cocrystal hydrate (ETP-THP-HYD 1:1:1). The cocrystals were structurally characterized by single crystal and powder X-ray diffraction, DSC and TGA thermal measurements, and IR...

THERMAL CHARACTERISTIC EVALUATION OF DIFFERENT ASCORBIC ACID CRYSTAL HABITS

Melting temperature (Tmelt) and enthalpy of fussion (ΔHf ) are important parameters to determine the quality and the thermal stability of active pharmaceutical ingredient (API) crystals. In this study, different habit of ascorbic acid was prepared by using different polar solvents namely water, methanol, ethanol and 2-propanol. Ascorbic acid crystal was then been physically and thermally characterised by using microscopic analysis, thermo gravimetric analysis (TGA) and differential scanning calometry analysis (DSC). This provides an insight into the formation of crystal habit across four different polar protic solvents. The ascorbic acid is found to grow as a cubic or prism crystal when grown in water that provides high hydrogen bond between solvent and solute. As the polarity of the solvents decrease, the hydrogen bond weaken and the width of the crystal become narrower, forming almost a needle like crystal. The thermal stability of ascorbic acid crystal is found to be the most stable when ascorbic acid is crystallized from water (prism) and the weakest from 2-propanol (needle) due to the molecule arrangement in crystal lattice in which resulted from decreasing intermolecular forces in the liquid phase

Does Electromagnetic Radiation affect drug stability?

Stability is one of the key determinant in assessing the quality, safety and efficacy of Active Pharmaceutical Ingredient (API) or Finished Pharmaceutical Product (FPP). Stability issues in a pharmaceutical products could result in physical, chemical changes in the finished products. Such degraded products could lead to treatment inefficiency, development of mild to severe adverse reactions in consumer, monetary loss and regulatory noncompliance. The stability of any API or FPP could be influenced by temperature, humidity, direct sun light, changes in storage conditions, frequency of single unit dispensing from bulk package, and other radiation related factors. Temperature is one of the key physical factors which affects drug stability and potency. For example, storage of insulin at 32˚C and above lose its potency after two weeks and on cold storage retains its potency for more than three weeks.1 Few of the pharmaceutical formulations are advised to store it in amber colour containers to prevent its degradation by direct sun light. It should be observed that the radiation related factors are expected to play a major role in affecting the stability of FPPs. The radiation related factors includes radiation from cellular towers, smart phones, mobiles, Wi-Fi supporting devices, electronic gadgets, particle radiation, acoustic radiation and gravitational radiation may also affect the stability of FPP. The effects of radiation gains much significance specifically in the current digital world, because the digital devices have become a part of our daily routine life. The effect of various radiation factors on the stability of APIs or FPPs is a major area of health concern that has to be given due importance. The current guidelines on stability assessments have not incorporated the effects of these radiations on APIs or FPPs. It is essential to study the effect of radiations on stability of any formulation to ensure it’s safety Read more...

Physicochemical screening for chemical stabilizer of erythropoietin to prevent its aggregation

ABSTRACTRecombinant protein aggregation is a problematic issue and can provoke immunological response. The aim of this study was to analyze the stability of erythropoietin (EPO), as a therapeutic protein expressed in mammalian cells, in the presence of different chemicals and find a specific stabilizer for EPO. The effects of several chemicals, including mannitol, betaine, trehalose, taurine, linoleic acid, beta-cyclodextrin, copper sulfate, spermidine, maltose, maltodextrin, sucrose, dextran, beta-alanine, myo-inositol, and cysteine, on protein stabilization through the thermally induced aggregation of EPO were monitored. Based on the results of turbidity assay for thermal aggregation, three different patterns were observed for protein stability of active pharmaceutical ingredient of EPO, namely, accelerated, dose-dependent, and inhibitory behaviors for aggregate formation due to treatment with spermidine, mannitol, and betaine, respectively. According to circular dichroism outcomes, EPO treatment with betaine and spermidine resulted in different helical contents of the secondary structure. Dynamic light scattering experiments indicated that treating EPO with betaine resulted in less protein aggregation due to freeze and thaw stresses. Betaine was able to stabilize EPO and inhibit its aggregation, as opposed to spermidine that induced protein aggregation.

Characterization of forced degradation products of canagliflozine by liquid chromatography/quadrupole time-of-flight tandem mass spectrometry and in silico toxicity predictions.

Forced degradation studies are useful for better understanding of the stability of active pharmaceutical ingredients and drugs and to generate information about drug degradation pathways and formation of degradation products (DPs). Identification of DPs plays a vital role in establishing the safety and therapeutic benefit of a drug. Canagliflozin (CAN) was subjected to different stress conditions as per International Conference on Harmonization guidelines (Q1A R2). All the DPs and the drug were well separated on an Aquity CSH C18 (100 × 2.1mm, 1.7 μm) column using acetonitrile-methanol (70:30, v/v) and formic acid in gradient mode. The same UPLC method was employed for LC/HRMS for the characterization of DPs. In addition, in silico toxicity was predicted for all the DPs by using TOPKAT and DEREK software tools. CAN was found to degrade under oxidative stress condition and formed DP1 and DP2. This is a typical case of degradation where co-solvents acetonitrile-water (50:50, v/v) and methanol-water (50:50, v/v) react with CAN under acid hydrolytic conditions leading to the formation of pseudo-DPs, DP3 and DP4, respectively. Among these, DP2 and DP3 showed ocular irritancy whereas DP1 showed skin sensitization. The drug was labile under oxidative stress condition. CAN reacted with co-solvent under acid hydrolytic conditions and gave pseudo-DPs. All the DPs were separated using UPLC and characterized by LC/QTOF/MS/MS. Toxicity of DPs was evaluated using TOPKAT and DEREK software tools.

From Drying Kinetics, Solvate Structure, Particle Morphology, and Modeling to Optimal Drying Protocol

The mechanistic understanding of three key active pharmaceutical ingredient (API) drying elements: drying kinetics, physical property control, and stability control, is critical for downstream formulation development and manufacture. The objective of this study was to collect drying kinetic data through the use of a laboratory integrated sorption chamber to elucidate the drying mechanism and thereby establish a drying model. In addition, the collection of drying kinetic data would provide a greater understanding of the solvent to API ratio as well as the API stability to help develop a large-scale drying protocol. The study material is an ethanol solvate (ethanolate) of the API. There is no fundamental crystal structure change upon drying of the solvate in the temperature range from 50 to 90 °C, and the drying kinetic data show that the molar ratio of ethanol to API is 1:1. This is confirmed by X-ray crystallography. An analysis of the drying kinetics showed that the diffusion of ethanol through the cryst...

Dependence of anticonvulsant activity of 1-aryl-1, 5-dihydro-4H-pyrazole (3,4-d) pyrimidine-4-one derivatives on biopharmaceutical factors

Background: We have synthesized three 5-R-1-aryl-1,5-dihydro-4Н-pyrazole(3,4-d)pyrimidine-4-one derivatives that previously have demonstrated powerful anticonvulsant activity. A great number of physicochemical factors are known to influence on bioavailability and stability of active pharmaceutical ingredients. Therefore the purpose of research was to determine the effect of purification technology and dispersibility of 5-R-1-aryl-1, 5-dihydro-4Н-pyrazole (3,4-d) pyrimidine-4-one derivatives on their anticonvulsant activity.Methods: The anticonvulsant effect of this compounds was studied in a model of pentylenetetrazole-induced seizure in mice.Results: The results obtained revealed the optimal solvent for recrystallization of compounds to be isopropanol: compounds, purified by recrystallization from isopropanol, had higher solubility in water and tween; also, they had a tendency to increase anticonvulsant activity. It was found that there is a significant dependence of the latter on compound’s dispersion - the smaller the size of crystals the higher anticonvulsant activity.Conclusions: The dependence of anticonvulsant activity of compounds on the degree of dispersion was proved: the smaller particle size the higher anticonvulsant activity. This can be explained by fast dissolution of fine-dispersed substances, thus increasing the bioavailability if the compounds studied.

Development Considerations for Nanocrystal Drug Products.

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

Prediction of the changes in drug dissolution from an immediate-release tablet containing two active pharmaceutical ingredients using an accelerated stability assessment program (ASAPprime®)

The computer program ASAPprime® has been used successfully for some time to predict the stability of active pharmaceutical ingredients (APIs) in solid-dosage forms. In this study, we have demonstrated that the ASAPprime® program can also be used to predict the slow-down in dissolution of two APIs in an immediate release tablet. The tablets were pre-equilibrated at 25 °C at different relative humidities (30–75 %), sealed in aluminum pouches and stored at temperatures ranging from 50–60 °C for 3, 7 or 14 days. The storage times were selected to encompass the time needed to produce a slowdown in dissolution such that the amount of the two APIs fell below the acceptance criteria of no less than 80 % dissolved in 20 min. Up to 6 months of stability data from a 40 °C/75%RH open dish study were also included in the modeling. The effects of temperature (T in °K) and relative humidity (RH) were then shown to be related to the isoconversion (IC) time by an empirical, modified Arrhenius equations, where IC is the time for the amount dissolved to equal 80 % of the label claim. These studies showed that while the slowdown in dissolution of API 2 was influenced more by the relative humidity than API 1, the overall slowdown in dissolution was more sensitive to changes in temperature than changes in relative humidity. In addition to showing that ASAPprime® could be used to model the effects of temperature and relative humidity on dissolution, the software was also used to demonstrate that no special precautions were necessary to protect the tablets from moisture and they could be stored in Aclar blisters®. It was also shown that the water content of the tablet was not a critical quality attribute and need not be included in the drug product specification.

Electrochemical oxidation coupled with liquid chromatography and mass spectrometry to study the oxidative stability of active pharmaceutical ingredients in solution: A comparison of off-line and on-line approaches

Stability studies of pharmaceutical drug products and pharmaceutical active substances are important to research and development in order to fully understand and maintain product quality and safety throughout its shelf-life. Oxidative forced degradation studies are among the different types of stability studies performed by the pharmaceutical industry in order to understand the intrinsic stability of drug molecules. We have been comparing the use of electrochemistry as an alternative oxidative forced degradation method to traditional forced degradation and accelerated stability studies. Using the electrochemical degradation approach the substrate oxidation takes place in a commercially available electrochemical cell and the effluent of the cell can be either a) directly infused into the mass spectrometer or b) injected in a chromatographic column for separation of the different products formed prior to the mass spectrometry analysis. To enable the study of large numbers of different experimental conditions and molecules we developed a new dual pump automated electrochemical screening platform. This system used a HPLC pump and autosampler to load and wash the electrochemical cell and deliver the oxidized sample plug to a second injection loop. This system enabled the automatic sequential analyses of large numbers of different solutions under varied experimental conditions without need for operator intervention during the run sequence. Here we describe the system and evaluate its performance using a test molecule with well characterized stability and compare results to those obtained using an off-line electrochemistry approach.

Anomalous size evolution of partially amorphized pharmaceutical particles during post-milling storage

Milling is simple and inexpensive method for particle size reduction. The micronization process such as fluid-energy impact mills (e.g. spiral jet mills and fluidized bed jet mills) is commonly used in the pharmaceutical industries to attain optimal/desire particle size distribution for pharmaceutical powders. However, this process may also cause several undesirable effects on active pharmaceutical ingredients (APIs) such as aggregation of fine particles, induction of electrostatic charges, mechanochemical transformation, defects on the surface of drug particles (amorphization) and changes in other physicochemical properties which may significantly affect the physical stability of API powders.In this study, the effect of milling-induced amorphization on the properties of APIs jet-milled at different energy-inputs (high (I), medium (II) and optimal (III)) provided from industry was investigated. Dynamic vapor sorption (DVS) technique has been established to quantify the amorphous content of industry milled APIs (I, II and III). A time-course study has been conducted to evaluate the physical stability of X-ray amorphous (generated by in-house cryo-milling as control) and three industrial samples I, II and III under accelerated stability test conditions (A=40°C/75%RH and B=25°C/55%RH) and any accompanying changes in key physicochemical properties such as crystallinity, agglomerate strength, particle size distribution (PSD) and morphology. In descending order, the amorphous content (%) of industrial API samples (milled different energy-inputs (high (I), medium (II) and optimal (III))) were ranked from I (50.9%), II (31.6%) to III (14.6%).Re-crystallization of X-ray amorphous and industrial samples was observed under both conditions A and B during storage of 13weeks. It was observed that there were changes in the particle size of APIs during post-micronization storage. There were reductions in particle size of all industrial samples under conditions A and B after 13weeks of storage. A possible explanation on the observation of anomalous particle size shift during post-milling storage was attributed to two different phenomena occurring at the same time and competing with each other. These two phenomena are called “surface re-crystallization” and “stress relaxation”. Re-crystallization of amorphous surface (observed from SEM) may lead to enlargement of particle size due to formation of solid bridges during storage. Microcompressor tester (MCT) analysis also suggested that the agglomerate strength increases during storage due to the surface re-crystallization. In case of particle size reduction, PSD analysis suggested that the milled agglomerates exhibited breakage pattern termed as localized disintegration whereby clusters of primary particles broke off from the outer surface of milled agglomerates. This was likely attributed to the energy-intensive micronization process that induces residual stresses, which propagate over time and lead to the breakage of particle agglomerates. Overall, the stress relaxation is more dominant than the re-crystallization and results in overall particle size reduction after storage.