Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8 mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid.

Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine (1), a Lophophora alkaloid, has been reported to have short-acting sleep-inducing properties in humans. In this study, we set out to evaluate various in vitro and in vivo properties of 1. We demonstrate that 1 undergoes slow metabolism; e.g. in mouse liver microsomes 65% remained, and in human liver microsomes virtually no metabolism was observed after 4 h. In mouse liver microsomes, two phase I metabolites were identified: 7-desmethylpellotine and pellotine-N-oxide. In mice, the two diastereomers of pellotine-O-glucuronide were additionally identified as phase II metabolites. Furthermore, we demonstrated by DESI-MSI that 1 readily enters the central nervous system of rodents. Furthermore, radioligand-displacement assays showed that 1 is selective for the serotonergic system and in particular the serotonin (5-HT)1D, 5-HT6, and 5-HT7 receptors, where it binds with affinities in the nanomolar range (117, 170, and 394 nM, respectively). Additionally, 1 was functionally characterized at 5-HT6 and 5-HT7, where it was found to be an agonist at the former (EC50 = 94 nM, Emax = 32%) and an inverse agonist at the latter (EC50 = 291 nM, Emax = -98.6). Finally, we demonstrated that 1 dose-dependently decreases locomotion in mice, inhibits REM sleep, and promotes sleep fragmentation. Thus, we suggest that pellotine itself, and not an active metabolite, is responsible for the hypnotic effects and that these effects are possibly mediated through modulation of serotonergic receptors.

Decoding the Postulated Entourage Effect of Medicinal Cannabis: What It Is and What It Isn't.

The 'entourage effect' term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the 'entourage effect' is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the 'entourage effect' from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the 'entourage effect' is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).

The concentration of lidocaine and mepivacaine measured in synovial fluid of different joints of horses after single intra-articular injection.

Objective: To determine the synovial fluid (SF) concentrations of lidocaine and mepivacaine after intra-articular injection with clinically relevant doses to the distal interphalangeal (DIP), metacarpophalangeal (MCP), middle carpal (MC), and tarsocrural (TC) joint at two different time points after injection in order to be able to compare concentrations with previously established concentrations associated with cytotoxicity and antimicrobial activity. Procedures: In the first of two experiments, 20 joints (5 MC, 5 MCP, 10 DIP joints) of five horses under general anesthesia were injected with clinically referenced doses of 2% lidocaine. Simultaneously, the horses had 19 joints (5 MC, 5 MCP, 9 DIP joints) injected with clinically referenced doses of 2% mepivacaine. Synovial fluid samples were collected ~7 min after injection. In experiment 2, 23 joints of seven horses under standing sedation were injected with clinically referenced doses of 2% lidocaine. Similarly, the horses had 21 joints injected with 2% mepivacaine. Synovial fluid samples were collected ~23 min after injection. The concentration of mepivacaine and lidocaine in the obtained SF samples was assessed using high-performance-liquid-chromatography with mass spectrometry detection (HPLC MS). Results: Synovial fluid was obtained 6.8 ± 1.5 (experiment 1) and 23 ± 4.3 (experiment 2) min following intra-articular injection of mepivacaine and lidocaine. Synovial fluid concentrations of experiment 1 for lidocaine and mepivaciane were 6.46-19.62 mg/mL (mean 11.96 ± SD 3.89 mg/mL) and 5.01-13.38 mg/mL (mean 8.18 ± SD 1.76 mg/mL), respectively. In experiment 2, concentrations were 2.94-10.40 mg/mL (mean 6.31± SD 2.23 mg/mL) for lidocaine and 2.10-8.70 mg/mL (mean 4.97 ± SD 1.77 mg/mL) for mepivacaine. Conclusions and clinical relevance: Intra-articular LA injections in horses resulted in SF concentrations above those previously associated with cytotoxic effects in vitro but also above those associated with beneficial antimicrobial activities. Local anesthetic concentration was 33-60% lower after 23 min (experiment 2) than after 7 min (experiment 1).

Clinical Research Evidence Supporting Administration and Dosing Recommendations of Medicinal Cannabis as Analgesic in Cancer Patients.

The analgesic potential of Cannabis sativa L.-based medicinal cannabis products for treatment of cancer associated chronic pains has gained increased interest in recent years. To ensure a controlled distribution of these products and investigate their therapeutic potential, several countries have established so-called pilot trials. Many doctors, however, are hesitant to prescribe medicinal cannabis primarily due to lack of research evidence regarding the products' efficacy, safety and thus questionable dosing guidelines. This review aims to elucidate clinical research supporting administration of medicinal cannabis in cancer patients for analgesic purposes. The cannabinoids' effects on the endocannabinoid system (ECS) and its implication in pain regulation is included to illustrate the complexity related to this research field. Published clinical studies on medicinal cannabis primarily consist of observational studies and only one pilot randomized controlled trial (RCT), where more RCTs exist on the cannabis-based product, Sativex® (GW Pharma Ltd., Cambridge, UK). The studies indicate analgesic potential, however non-significantly, for most patients and with acceptable safety profile. Summarizing, high-quality RCTs are scarce in this research field, and the limitations of the observational studies complicates interpretation of clinical outcomes. Despite discrepancy among the studies, they do show indications for administration and dosing regimens providing analgesic effects for some cancer patients.

Data-Enriched Edible Pharmaceuticals (DEEP) with Bespoke Design, Dose and Drug Release.

Data-enriched edible pharmaceuticals (DEEP) is an approach to obtain personalized medicine, in terms of flexible and precise drug doses, while at the same time containing data, embedded in quick response (QR) codes at a single dosage unit level. The aim of this study was to fabricate DEEP with a patient-tailored dose, modify drug release and design to meet patients' preferences. It also aimed to investigate physical stability in terms of the readability of QR code patterns of DEEP during storage. Cannabinoids, namely, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were used as the model active pharmaceutical ingredients (APIs). Three different substrates and two colorants for the ink were tested for their suitability to fabricate DEEP by desktop inkjet printing. Flexible doses and customizable designs of DEEP were obtained by manipulating the digital design of the QR code, particularly, by exploring different pattern types, embedded images and the physical size of the QR code pattern. Modification of the release of both APIs from DEEP was achieved by applying a hydroxypropyl cellulose (HPC) polymer coating. The appearance and readability of uncoated and polymer-coated DEEP did not change on storage in cold and dry conditions; however, the HPC polymer layer was insufficient in preserving the readability of the QR code pattern in the extreme storage condition (40 °C and 75% relative humidity). To sum up, the DEEP concept provides opportunities for the personalization of medicines, considering also patients' preferences.

Data-enriched edible pharmaceuticals (DEEP) of medical cannabis by inkjet printing.

Medical cannabis has shown to be effective in various diseases that have not successfully been treated with other marketed drug products. However, the dose of cannabis is highly individual and additionally, medical cannabis is prone to misuse. To combat these challenges, the concept of data-enriched edible pharmaceuticals (DEEP) is introduced. Quick Response (QR) code patterns containing lipophilic cannabinoids, i.e., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), were printed using a desktop inkjet printer. This allows for simultaneously printing an individual dose and encapsulating information relevant to the end-users and other stakeholders in a single dosage unit, which is readable by a standard smartphone. Different doses of CBD and THC were incorporated in the DEEP by printing various (1-10) layers of the cannabinoid-containing ink on porous substrates, i.e., solid foams, prepared by solvent casting and subsequent freeze-drying. The printed DEEP were still readable after 8 weeks of storage in dry and cold conditions. This approach of 'in-drug labeling' instead of 'drug package labeling' provides a new possibility for developing a more efficient supply chain of pharmaceuticals and safer medication schemes by increasing the traceability of drug products at a single dosage unit level.

Medication Tracking: Design and Fabrication of a Dry Powder Inhaler with Integrated Acoustic Element by 3D Printing.

PURPOSE: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler. METHODS: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression. RESULTS: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking. CONCLUSIONS: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Historical chemical annotations of Cinchona bark collections are comparable to results from current day high-pressure liquid chromatography technologies.

ETHNOPHARMACOLOGICAL RELEVANCE: Species of the genus Cinchona (Rubiaceae) have been used in traditional medicine, and as a source for quinine since its discovery as an effective medicine against malaria in the 17th century. Despite being the sole cure of malaria for almost 350 years, little is known about the chemical diversity between and within species of the antimalarial alkaloids found in the bark. Extensive historical Cinchona bark collections housed at the Royal Botanic Gardens, Kew, UK, and in other museums may shed new light on the alkaloid chemistry of the Cinchona genus and the history of the quest for the most effective Cinchona barks. AIM OF THE STUDY: We used High-Pressure Liquid Chromatography (HPLC) coupled with fluorescence detection (FLD) to reanalyze a set of Cinchona barks originally annotated for the four major quinine alkaloids by John Eliot Howard and others more than 150 years ago. MATERIALS AND METHODS: We performed an archival search on the Cinchona bark collections in the Economic Botany Collection housed in Kew, focusing on those with historical alkaloid content information. Then, we performed HPLC analysis of the bark samples to separate and quantify the four major quinine alkaloids and the total alkaloid content using fluorescence detection. Correlations between historic and current annotations were calculated using Spearman's rank correlation coefficient, before paired comparisons were performed using Wilcox rank sum tests. The effects of source were explored using generalized linear modelling (GLM), before the significance of each parameter in predicting alkaloid concentrations were assessed using chi-square tests as likelihood ratio testing (LRT) models. RESULTS: The total alkaloid content estimation obtained by our HPLC analysis was comparatively similar to the historical chemical annotations made by Howard. Additionally, the quantity of two of the major alkaloids, quinine and cinchonine, and the total content of the four alkaloids obtained were significantly similar between the historical and current day analysis using linear regression. CONCLUSIONS: This study demonstrates that the historical chemical analysis by Howard and current day HPLC alkaloid content estimations are comparable. Current day HPLC analysis thus provide a realistic estimate of the alkaloid contents in the historical bark samples at the time of sampling more than 150 years ago. Museum collections provide a powerful but underused source of material for understanding early use and collecting history as well as for comparative analyses with current day samples.

Using Potentiometric Free Drug Sensors to Determine the Free Concentration of Ionizable Drugs in Colloidal Systems.

The present study investigates the use of free drug sensors (FDS) to measure free ionized drug concentrations in colloidal systems, including micellar solutions, emulsions, and lipid formulations during in vitro lipolysis. Diphenhydramine hydrochloride (DPH) and loperamide hydrochloride (LOP) were selected as model drugs. Self-diffusion nuclear magnetic resonance studies were performed and confirmed the entrapment of drugs in micelles in Brij 35 and sodium taurodeoxycholate (TDC)/phosphatidylcholine (PC) micellar solutions. The FDS measurements indicated that with a constant level of drug, the percentage of free DPH and LOP decreased from 84% to 57% and from 51% to 18%, respectively, as the concentration of Brij 35 was increased from 4.7 to 22 mM; and from 99% to 46% and from 100% to 21%, respectively, as the concentration of TDC/PC was increased from 0.49/0.04 to 8.85/0.78 mM. During the in vitro lipolysis of a lipid formulation, free drug concentration decreased with lipolysis time. The percentage of free DPH was higher than for LOP in the same colloidal system because DPH is less lipophilic than LOP. The study showed that FDS can be used to monitor the free drug concentration in colloidal systems with fast response, no sample treatment and simple data analysis.

An Optimised Method for Routine Separation and Quantification of Major Alkaloids in Cortex Cinchona by HPLC Coupled with UV and Fluorescence Detection.

INTRODUCTION: Authentication of herbal products to ensure efficacy and safety require efficient separation and quantification of constituents. Standard assays for Cinchona bark used for the treatment of malaria and production of quinine, either use only spectrophotometry to detect two pairs of diastereoisomers of quinine and cinchonine type alkaloids (European Pharmacopoeia, Ph.Eur.) or liquid chromatography primarily optimised for detection of the four major alkaloids. However, numerous minor alkaloids occur in Cinchona and related species and efficient separation including gradient elution is necessary in order to obtain the full pattern of constituents in bark samples. OBJECTIVE: To develop an optimised HPLC method for separation and quantitative analysis of the four major alkaloids in Cinchona bark using UV detection. METHODOLOGY: Dimethyl sulphoxide (DMSO) extracts of 50 mg of pulverised barks were prepared using ultrasonication. The chromatographic separation was performed on an XB-C18 column packed with 2.6 µm particles. Gradient elution using an ammonium formate buffer and methanol as organic modifier over 26 min was based on non-chiral separation of the diastereoisomers and the high solvent selectivity of methanol. Post column UV detection was performed at 250 nm and 330 nm. Fluorescence detection was performed using 330 nm for excitation and 420 nm for emission. RESULTS: The optimised HPLC method facilitates efficient separation and quantification of the four major alkaloids in 26 min with a limit of quantification of 5 µg/g from 50 mg bark sample. CONCLUSION: The optimised HPLC method offers a simple and efficient quantification of the four major alkaloids. Copyright © 2017 John Wiley & Sons, Ltd.

Phylogeny Predicts the Quantity of Antimalarial Alkaloids within the Iconic Yellow Cinchona Bark (Rubiaceae: Cinchona calisaya).

Considerable inter- and intraspecific variation with respect to the quantity and composition of plant natural products exists. The processes that drive this variation remain largely unknown. Understanding which factors determine chemical diversity has the potential to shed light on plant defenses against herbivores and diseases and accelerate drug discovery. For centuries, Cinchona alkaloids were the primary treatment of malaria. Using Cinchona calisaya as a model, we generated genetic profiles of leaf samples from four plastid (trnL-F, matK, rps16, and ndhF) and one nuclear (ITS) DNA regions from twenty-two C. calisaya stands sampled in the Yungas region of Bolivia. Climatic and soil parameters were characterized and bark samples were analyzed for content of the four major alkaloids using HPLC-UV to explore the utility of evolutionary history (phylogeny) in determining variation within species of these compounds under natural conditions. A significant phylogenetic signal was found for the content of two out of four major Cinchona alkaloids (quinine and cinchonidine) and their total content. Climatic parameters, primarily driven by changing altitude, predicted 20.2% of the overall alkaloid variation, and geographical separation accounted for a further 9.7%. A clade of high alkaloid producing trees was identified that spanned a narrow range of altitudes, from 1,100 to 1,350 m. However, climate expressed by altitude was not a significant driver when accounting for phylogeny, suggesting that the chemical diversity is primarily driven by phylogeny. Comparisons of the relative effects of both environmental and genetic variability in determining plant chemical diversity have scarcely been performed at the genotypic level. In this study we demonstrate there is an essential need to do so if the extensive genotypic variation in plant biochemistry is to be fully understood.

Two simple cleanup methods combined with LC-MS/MS for quantification of steroid hormones in in vivo and in vitro assays.

Measuring both progestagens, androgens, corticosteroids as well as estrogens with a single method makes it possible to investigate the effects of endocrine-disrupting chemicals (EDCs) on the main pathways in the mammalian steroidogenesis. This paper presents two simple methods for the determination of the major steroid hormones in biological matrixes using liquid chromatography tandem mass spectrometry (LC-MS(2)). A novel method was developed for the determination of 14 steroids in the H295R in vitro assay without the need for solid phase extraction (SPE) purification prior to LC-MS(2) analysis. The in vitro assay was validated by exposing H295R cells to prochloraz for inhibiting steroid hormone secretion and by exposing cells to forskolin for inducing steroid hormone secretion. The developed method fulfills the recommendations for the H295R assay suggested by the OECD. Furthermore, a simple off-line SPE methodology was developed for the necessary clean-up of in vivo assays. Samples, such as gonad tissue, plasma and serum, are complex biological matrixes, and the SPE methodology was optimized to remove salts and proteins prior to elution of target analytes. At the same time, lipophilic compounds were retained on the SPE cartridge during elution. This, combined with the multi-steroid LC-MS(2) method, made it possible to determine 10 steroids in male Sprague-Dawley rat gonad tissue. Furthermore, it was possible to quantify 6 steroids in the plasma. In general, the observed concentration of steroid hormones in plasma, testes, and H295R cell medium corresponded well with previous studies. The off-line SPE method was validated using spiked charcoal-stripped serum. Method recovery, accuracy, precision and robustness were all good. Instrument sensitivity was in the range of 55-530 pg/mL (LLOQ).

In vitro release studies of insulin from lipid implants in solution and in a hydrogel matrix mimicking the subcutis.

Widely accepted in vitro methodologies for sustained release parenteral drug formulations remain to be established. Hydrogels have been proposed as a release matrix more closely resembling the in vivo conditions for formulations intended for subcutaneous administration. The perspective of the current work was to investigate the feasibility of developing UV imaging-based in vitro methods enabling visualization and characterization of drug release and transport of protein therapeutics intended for subcutaneous administration. Specifically, the objectives were to prepare lipid implants providing sustained release of the model protein insulin and investigate the release into 0.5% (w/v) agarose hydrogels, pH7.40, using UV imaging- and a gel sampling-based release testing method. These results were compared to insulin release into well agitated buffer solution. Irrespective of the applied in vitro release method, the insulin release from Sterotex implants with a drug load of 20% (w/w) was faster as compared to the release from implants with a load of 10% (w/w), most likely due to the higher porosity of the implants with increasing drug load. Insulin release from 10% (w/w) implants into agitated solution was faster as compared to release into agarose hydrogel. This was ascribed to the additional mass transfer resistance provided by the agarose hydrogel. Interestingly, the release profiles of insulin from implants with an initial drug load of 20% (w/w) obtained by the three in vitro methods were relatively similar. The gel-based methods, in particular UV imaging, enable monitoring local drug concentrations in the vicinity of the implant over time thereby facilitating assessment of, e.g., sink conditions. The study highlights that the selection of the in vitro release method should take into account various factors including mass transport, drug stability, data analysis and simplicity of the methodology.

Formation Mechanism of Coamorphous Drug-Amino Acid Mixtures.

Two coamorphous drug-amino acid systems, indomethacin-tryptophan (Ind-Trp) and furosemide-tryptophan (Fur-Trp), were analyzed toward their ease of amorphization and mechanism of coamorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar ratio were milled for varying times, and their physicochemical properties were investigated using XRPD, (13)C solid state NMR (ssNMR), and DSC. Comilling the drug with the amino acid reduced the milling time required to obtain an amorphous powder from more than 90 min in the case of the pure drugs to 30 min for the coamorphous powders. Amorphization was observed as reductions in XRPD reflections and was additionally quantified based on normalized principal component analysis (PCA) scores of the ssNMR spectra. Furthermore, the evolution in the glass temperature (Tg) of the coamorphous systems over time indicated complete coamorphization after 30 min of milling. Based on the DSC data it was possible to identify the formation mechanism of the two coamorphous systems. The Tg position of the samples suggested that coamorphous Ind-Trp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur-Trp was formed by the drug being dissolved in the amorphous amino acid.

Evaluation of microwave oven heating for prediction of drug-excipient compatibilities and accelerated stability studies.

Microwave ovens have been used extensively in organic synthesis in order to accelerate reaction rates. Here, a set up comprising a microwave oven combined with silicon carbide (SiC) plates for the controlled microwave heating of model formulations has been applied in order to investigate, if a microwave oven is applicable for accelerated drug stability testing. Chemical interactions were investigated in three selected model formulations of drug and excipients regarding the formation of ester and amide reaction products. In the accelerated stability studies, a design of experiments (DoE) approach was applied in order to be able to rank excipients regarding reactivity: Study A: cetirizine with PEG 400, sorbitol, glycerol and propylene glycol. Study B: 6-aminocaproic acid with citrate, acetate, tartrate and gluconate. Study C: atenolol with citric, tartaric, malic, glutaric, and sorbic acid. The model formulations were representative for oral solutions (co-solvents), parenteral solutions (buffer species) and solid dosage forms (organic acids applicable for solubility enhancement). The DoE studies showed overall that the same impurities were generated by microwave oven heating leading to temperatures between 150°C and 180°C as compared to accelerated stability studies performed at 40°C and 80°C using a conventional oven. Ranking of the reactivity of the excipients could be made in the DoE studies performed at 150-180°C, which was representative for the ranking obtained after storage at 40°C and 80°C. It was possible to reduce the time needed for drug-excipient compatibility testing of the three model formulations from weeks to less than an hour in the three case studies. The microwave oven is therefore considered to be an interesting alternative to conventional thermal techniques for the investigation of drug-excipient interactions during preformulation.

Structure elucidation and quantification of impurities formed between 6-aminocaproic acid and the excipients citric acid and sorbitol in an oral solution using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy.

Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50°C, 60°C, 70°C and 80°C as well as at 20°C. It has previously been reported that the commonly employed citric acid is a reactive excipient, and it is therefore important to thoroughly investigate a possible reaction between 6-aminocaproic acid and citric acid. The current study revealed the formation of 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid between 6-aminocaproic acid and citric acid by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectroscopy (NMR). Less than 0.03% of 6-aminocaproic acid was converted to 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid after 30 days of storage at 80°C. Degradation products of 6-aminocaproic acid were also observed after storage at the applied temperatures, e.g., dimer, trimer and cyclized 6-aminocaproic acid, i.e., caprolactam. No reaction products between D-sorbitol and 6-aminocaproic acid could be observed. 3-Hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid, dimer and caprolactam were also observed after storage at 20°C for 3 months. The findings imply that an oral solution of 6-aminocaproic acid is relatively stable at 20°C at the pH values 4.00 and 5.00 as suggested in the USP for oral formulations. Compliance with the ICH guideline Q3B is expected.

Real-time UV imaging identifies the role of pH in insulin dissolution behavior in hydrogel-based subcutaneous tissue surrogate.

For parenteral biopharmaceuticals, subcutaneous diffusion and, in the case of solid implants or suspensions, dissolution may govern the clinical profile of the drug product. Insight into the dissolution and diffusion processes of biopharmaceuticals after parenteral administration is fundamental in the development of new protein drug formulations. Using insulin as a model compound, the aim of this work was to develop a UV imaging-based method to study the real-time dissolution and diffusion behavior of solid protein drugs under stagnant conditions in a hydrogel matrix mimicking the subcutaneous tissue. Dissolution of proteins and peptides is a complex phenomenon as it may be coupled to the complicated acid base properties of these substances. UV imaging allowed the real-time dissolution and diffusion processes of insulin at different pH values and of different insulins to be studied. Dissolution rates were obtained, and the quantitative performance of the developed UV imaging method was verified. It was shown that the UV imaging dissolution method was able to differentiate between the behavior of different insulins and that human insulin dissolution was highly dependent on pH. pH effects in the microenvironment of the human insulin compacts at pH 7.40 and 3.00 were observed by UV-Vis imaging, explaining the different dissolution kinetics of human insulin at pH 7.40 and 3.00 as compared to pH 5.40. In conclusion, UV-Vis imaging may be a useful tool for studying dissolution, diffusion and pH effects in the vicinity of solid protein drug in a hydrogel matrix with the aim of achieving a better understanding of in vivo dissolution processes.

An Efficient, Robust, and Inexpensive Grinding Device for Herbal Samples like Cinchona Bark.

An effective, robust, and inexpensive grinding device for the grinding of herb samples like bark and roots was developed by rebuilding a commercially available coffee grinder. The grinder was constructed to be able to provide various particle sizes, to be easy to clean, and to have a minimum of dead volume. The recovery of the sample when grinding as little as 50 mg of crude Cinchona bark was about 60%. Grinding is performed in seconds with no rise in temperature, and the grinder is easily disassembled to be cleaned. The influence of the particle size of the obtained powders on the recovery of analytes in extracts of Cinchona bark was investigated using HPLC.

Structural basis for the transformation pathways of the sodium naproxen anhydrate-hydrate system.

Crystal structures are presented for two dihydrate polymorphs (DH-I and DH-II) of the non-steroidal anti-inflammatory drug sodium (S)-naproxen. The structure of DH-I is determined from twinned single crystals obtained by solution crystallization. DH-II is obtained by solid-state routes, and its structure is derived using powder X-ray diffraction, solid-state (13)C and (23)Na MAS NMR, and molecular modelling. The validity of both structures is supported by dispersion-corrected density functional theory (DFT-D) calculations. The structures of DH-I and DH-II, and in particular their relationships to the monohydrate (MH) and anhydrate (AH) structures, provide a basis to rationalize the observed transformation pathways in the sodium (S)-naproxen anhydrate-hydrate system. All structures contain Na(+)/carboxylate/H2O sections, alternating with sections containing the naproxen molecules. The structure of DH-I is essentially identical to MH in the naproxen region, containing face-to-face arrangements of the naphthalene rings, whereas the structure of DH-II is comparable to AH in the naproxen region, containing edge-to-face arrangements of the naphthalene rings. This structural similarity permits topotactic transformation between AH and DH-II, and between MH and DH-I, but requires re-organization of the naproxen molecules for transformation between any other pair of structures. The topotactic pathways dominate at room temperature or below, while the non-topotactic pathways become active at higher temperatures. Thermochemical data for the dehydration processes are rationalized in the light of this new structural information.