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Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none of these tissues is duloxetine or its metabolites homogeneously distributed, which has implications for both efficacy and toxicity. We found duloxetine to be similarly distributed in spleen red pulp and white pulp but differentially distributed in different anatomic regions of the liver, kidney, and brain, with dose-dependent patterns. Comparison with hematoxylin and eosin staining of tissue sections reveals that the ion images of endogenous lipids help delineate anatomic regions in the brain and kidney, while heme ion images assist in differentiating regions within the spleen. These endogenous metabolites may serve as a valuable resource for examining the spatial distribution of other drugs in tissues when staining images are not available. These findings may facilitate future mechanistic studies of the therapeutic and adverse effects of duloxetine. In the current work, we did not perform absolute quantification of duloxetine, which will be reported in due course.SIGNIFICANCE STATEMENTThe study utilized imaging mass spectrometry to examine the spatial distribution of duloxetine and its primary metabolites in mouse brain, liver, kidney, and spleen. These results may pave the way for future investigations into the mechanisms behind duloxetine's therapeutic and adverse effects. Furthermore, the mass spectrometry images of specific endogenous metabolites such as heme could be valuable in analyzing the spatial distribution of other drugs within tissues in scenarios where histological staining images are unavailable.

Electronic health records (EHRs) have contributed to increased workloads for clinicians. Ambient artificial intelligence (AI) tools offer potential solutions, aiming to streamline clinical documentation and alleviate cognitive strain on healthcare providers.

A clinical study was initiated in response to patients’ complaints, supported by the treating physicians, of suspected differences in efficacy among multisource levothyroxine sodium tablets marketed in Egypt. The study design was a multiple dose (100μg levothyroxine sodium tablet once daily for 6 months) and involved 50 primary hypothyroidism female patients (5 equal groups). Tablets administered included five tablet batches (two brands, three origin locations) purchased from local pharmacies in Alexandria. Assessment parameters (measured on consecutive visits) included the thyroid stimulating hormone, total and free levothyroxine. Tablet dissolution rate was determined (BP/EP 2014 & USP 2014). In vitro vs in vivovscorrelations were developed. Clinical and pharmaceutical data confirmed inter-brand and inter-source differences in efficacy. Correlations examined indicated potential usefulness of in vitro dissolution test in detecting poor performing levothyroxine sodium tablets during shelf life.

Pexidartinib (PEX, TURALIO), a selective and potent inhibitor of the macrophage colony-stimulating factor-1 receptor, has been approved for the treatment of tenosynovial giant cell tumor. However, frequent and severe adverse effects have been reported in the clinic, resulting in a boxed warning on PEX for its risk of liver injury. The mechanisms underlying PEX-related hepatotoxicity, particularly metabolism-related toxicity, remain unknown. In the current study, the metabolic activation of PEX was investigated in human/mouse liver microsomes (HLM/MLM) and primary human hepatocytes (PHH) using glutathione (GSH) and methoxyamine (NH2OMe) as trapping reagents. A total of 11 PEX-GSH and 7 PEX-NH2OMe adducts were identified in HLM/MLM using an LC–MS-based metabolomics approach. Additionally, 4 PEX-GSH adducts were detected in the PHH. CYP3A4 and CYP3A5 were identified as the primary enzymes responsible for the formation of these adducts using recombinant human P450s and CYP3A chemical inhibitor ketoconazole. Overall, our studies suggested that PEX metabolism can produce reactive metabolites mediated by CYP3A, and the association of the reactive metabolites with PEX hepatotoxicity needs to be further studied.

The adsorption of atropine and hyoscine by magnesium trisilicate has been studied. At relatively low initial concentrations the adsorption data were shown to fit a Langmuir plot and values for monolayer adsorption were 14·9 and 3·8 mg g−1for atropine and hyoscine respectively. The extent of adsorption was increased at higher initial concentrations due to multilayer formation. The presence of either sodium citrate or sodium phosphate suppressed the adsorption. Elution of the adsorbed alkaloid was dependent on the pH of medium used and followed the order: 0·05nHCl (pH 1·5) >0·01nHCl (pH 2·1) > water (pH 5·5). Due to the dissolution of magnesium trisilicate, at 37° in 0·05nHCl, neither the rate of acid uptake nor the acid absorption test of the adsorbent were significantly reduced by the adsorption of either alkaloid. In the B.P.C. mixture of magnesium trisilicate and belladonna, almost complete adsorption of hyoscyamine occurred and the elution of the adsorbed alkaloid depended on the level of hydrochloric acid in the elution medium used.

The adsorption of digoxin and digitoxin by some antacids has been investigated. Magnesium trisilicate showed the highest adsorptive effect, the extent of adsorption being up to 99 % for the two glycosides. The calculated values of monolayer adsorption were 0·93 and 1·36 mg g-1for digoxin and digitoxin respectively. At 37° only partial elution of adsorbed glycosides occurred in 0·2N HCl due to re-adsorption on the hydrated silica gel formed. Antacid preparations containing magnesium trisilicate adsorbed digoxin from a paediatric elixir to the extent of about 95%. Dissolution of digoxin tablets was similarly affected since almost complete suppression of dissolution occurred in the presence of 0·5 g magnesium trisilicate per 0·25 mg digoxin tablet. The effect of antacids, when concurrently administered with oral digoxin, on the bioavailability of the drug, is discussed.

A study has been carried out to investigate the dissolution rate profiles of twelve batches of sugar-coated phenylbutazone tablets belonging to four commercial brands. Using the rotating basket method, significant inter-brand and inter-batch variations in dissolution rates were found. Only two batches of one brand passed the B.P. dissolution limit whilst other batches had percentages dissolution between 0.3 and 58 after 45 min. Batches with poor dissolution characteristics exhibited significant tablet-to-tablet variations in dissolution rates; a finding which was not observed in the relatively fast-dissolving batches. When the paddle method was substituted for the B.P. basket method, the dissolution rates were relatively faster but similar dissolution failure was found. However, the tablet-to-tablet dissolution variability was decreased in some of the batches. The observed differences in dissolution rates of the batches examined were unrelated to their disintegration times. Inspite of the poor dissolution characteristics of most of the batches studied, no apparent chemical degradation was found. It is recommended that when evaluating the dissolution rates of brands of phenylbutazone tablets, a number of batches from each brand should be tested.

A reverse phase HPLC procedure is described for the determination of chloramphenicol and its hydrolytic product, 2-amino-1-(4-nitrophenyl)-propane-1,3-diol. The method was validated for reproducibility, linearity and recovery for both components. It was successfully applied to monitor post-marketing stability of ten batches of chloramphenicol ophthalmic solutions stored at room temperature. As compared to the BP method using solvent extraction and UV measurements, for the determination of chloramphenicol and its hydrolytic product in chloramphenicol eye drops, the suggested procedure was found to be relatively more accurate, precise and less time-consuming.

An investigation was carried out of the in-vitro adsorption of a low-dose model drug (riboflavine) by three typzs of kaolin, attapulgite, magnesium trisilicate and a grade of magnesium aluminium silicate (veegumR. The adsorption experiments were designed under conditions simulating in-vivo with respect to variations in pH values, volume of the adsorption medium, and the presence of electrolytes, a hydrophilic colloid and a surfactant. Under all conditions examined, riboflavine adsorption followed the sequence veegum attapulgite kaolin magnesium trisilicateThe presence of either veegumR (1 g) or kaolin (4 g) in the medium reduced the level of drug in solution during dissolution rate testing of capsules. Desorption results suggest only partial release of the adsorbed drug. The results obtained emphasiz,e the strong uptake of a potent ionic drug by the various silicates commonly used in pharmacy.

In human volunteers, both the rate and extent of urinary excretion of riboflavine were significantly reduced (p<0.05) when attapulgite was co-administered with the drug. About 50% reduction occurred in the cumulative amount excreted following the concurrent administration of 10 mg riboflavine in solution form and 2 g of regular attapulgite. The co-administration of the drug with a 30 ml dose of a commercial antidiarrheal suspension containing 10% activated attapulgite and 3% colloidal attapulgite produced a relatively lesser effect; the reduction in extent of absorption being 40%. No statistically-significant effect was found when the adsorbent was ingested 2 h prior to the drug. The observed reduction in drug bioavailability in the presence of attqapulgite to the significant uptake of the drug by the adsorbent.

A study has been made to examine the stability and dissolution rates of prednisolone, prednisone and hydrocortisone formulated as solid dispersions in polyethylene glycols. Of the five PEG samples used, three enhanced the chemical instability of the steroids; the effect being dependent on the PEG sample and storage conditions of the solid dispersions. Dissolution rates of the steroids were relatively fast from the solid dispersions and showed no significant changes upon storage. Using two methods of analysis (direct UV spectrophotometry and the USP blue tetrazolium method), it is concluded that the chemical instability of the steroids in some PEG samples was due to alterations in the dihydroxy acetone side chain. One of the decomposition products found appeared to be an acidic compound resulting from oxidation of the C17 side chain. The oxidation is presumably accelerated by a peroxide impurity in PEG samples.

An improved method is described for the preparation of gelatin coacervate microcapsules containing sulphamerazine as a fine deflocculated powder. The factors which control both the coacervation step and the recovery of the microcapsules are discussed. The in vitrorelease of sulphamerazine from microcapsules of different wall thickness which had been hardened by formaldehyde under different conditions has been studied. The method of preparation gave a high percentage of encapsulated material in comparison with other recovery techniques.

Phase boundary determination, coacervate volume measurements and analysis of the phases have been made to assess the influence of pH on the coacervation of gelatin solutions by ethanol and sodium sulphate. Coacervation was found to be pH dependent. In the ethanol system coacervation was noticeable only within a pH range in the vicinity of the isoionic point; at other pH values either a viscous gel phase or floccules occurred. In the sodium sulphate system, coacervation occurred at all pH values examined. The effect of pH in changing the overall charge on the gelatin molecule is explained in relation to the formation of gelatin coacervates. Finally, the role of the coacervate phase in the microencapsulation of oil and solid particulates is discussed.

In the ethanol system the electrolytes had a suppressive effect on the coacervation of isoionic gelatin, whilst at other pH values the phenomenon was favoured in the presence of polyvalent ions. In the sodium sulphate system the added electrolytes produced insignificant effects. The similarity between the systems studied and the complex coacervating system: gelatin(+)-water-acacia(−)is discussed.

The influence of molecular weight on coacervation in the system iso-electric gelatin: ethanol: water has been studied. The minimum concentration of ethanol required to produce coacervation decreased as the molecular weight of the gelatin increased. Analysis of the coacervate phase showed that the ethanol content was approximately constant and independent of both the molecular weight of the gelatin and the total concentration of ethanol in the system.

The application of the B.P. disintegration apparatus in dissolution rate studies has been examined. The dissolution profiles of some brands of chloramphenicol capsules and tolbutamide tablets have been examined at various tube speeds with and without the guided disc. For both drugs a tube speed of 20 strokes/min gave the optimum difference in dissolution rates. The effect of the guided disc depended on the disintegration time of the product tested. For poorly disintegrating products the use of the guided disc resulted in about twofold increase in dissolution whilst insignificant effect was found for products with fast dissolution rate.

The uptake of benzoic acid on sulphadimidine particles has been investigated. Depending on the concentration of sulphadimidine in the system, benzoic acid was adsorbed to the extent of 94%. Data from the adsorption experiments were shown to fit a Langmuir plot for systems containing up to 0.2 g 100 ml−1sulphadimidine. The suppressive effect of three hydrophilic polymers on adsorption was studied; the results followed the sequence: Polyvinylpyrrolidone (PVP) > methylcellulose > sodium carboxymethylcellulose. Dialysis experiments revealed that, within the range of concentrations used, neither PVP nor methylcellulose was significantly bound to benzoic acid.

Some steroids used in oral contraceptives were adsorbed significantly by magnesium trisilicate. The adsorption affinity followed the sequence: ethindrone>mestranol>norethindrone>ethinyl estradiol. Adsorption data obtained at relatively low initial concentrations fitted a Langmuir plot; the values for monolayer adsorption ranged between 0.24 and 0.32mg/g. At higher concentrations of the steroids, multilayer adsorption occurred. The results of desorption experiments made at 37° in water and 0.05 NHC1 suggested that desorption was incomplete and depended on the amount of steroid adsorbed. During the dissolution testing of a brand of contraceptive tablets containing norethindrone acetate, the presence of 0.5% (w/v) magnesium trisilicate in the medium resulted in almost complete reduction in the amount of the steroid remaining in solution after 1 hr.

The suppressive effect of polyvinylpyrrolidone on benzoic acid adsorption by sulfamethazine was found to be time dependent. First-order plots showed that benzoic acid apparently diffused from the bulk to the sulfonamide surface through the polymeric “protective” film; therefore, the effect was dependent on the polymer–sulfonamide ratio. An increase in the polymer concentration slowed down the rate of benzoic acid migration. This effect cannot be attributable solely to an increase in bulk viscosity since nonpolymeric viscosity-imparting agents, e.g., glycerol and syrup, did not appreciably inhibit adsorption.

The adsorption of benzoic acid on sulfamethazine particles was found to be pH dependent. At pH values above 4.2 (the pKa of benzoic acid), a gradual suppression of the adsorption occurred; at pH 4.9 and above, no adsorption was noted. The effect of sodium citrate on adsorption is attributable to pH and ionic strength effects. Citric acid had an insignificant effect on the adsorption. The role of pH and citrate ions on the dissolution of sulfamethazine in this system is discussed.

A selective nonisotopic assay was used to investigate the digoxin hydrolysis rates at 37 ± 0.1° over the pH1.1–2.2 range. The colorimetric method adopted is based on the use of a xanthydrol reagent after extraction with chloroform. The spectrofluorometric method specified in the dissolution test for digoxin tablets was nonspecific because of digoxigenin interference. Digoxin hydrolysis followed specific acid hydrolysis, and Kvalues of the apparent first-order reaction varied from 0.0357 to 0.0027min−1over the pH range used. The effect of the dissolution medium on digoxin stability during the dissolution tests of the tablets also was studied. Water (the BP medium) and 0.6% HCl (the USP medium) were compared using the fluorometric method and the xanthydrol method. In the USP medium (pH1.3), no hydrolysis was revealed by the fluorometric estimation whereas the xanthydrol method showed about 74% hydrolysis. In water, the two methods revealed no hydrolysis. The extent of hydrolysis after 1hr in the USP medium was studied using three brands of digoxin tablets of differing dissolution characteristics. The fast dissolving brand showed relatively more hydrolysis than the slow dissolving tablets.

Following the acid-dye technique, hyoscyamine (or atropine) could be selectively determined in the presence of scopolamine, using bromcresol purple at pH 6.6. Total alkaloids were determined using bromthymol blue at pH 5.6. By referring to calibration curves of the two alkaloids with the appropriate dye, the concentration of each alkaloid in the mixture could be computed. The suggested procedure was adopted to analyze the two alkaloids in synthetic mixtures. As low as 0.05mg. of each alkaloid could be estimated, with average percentage recoveries of 98.6 and 101.5 for hyoscyamine and scopolamine, respectively. Tincture of belladonna was assayed following a modification of the suggested method. The results obtained were comparable with those obtained following the BP method.

Both the equilibrium solubility and dissolution rate of sulfamethazine were remarkably inhibited in the presence of benzoic acid. The effect was dependent on the concentrations of both the benzoic acid and sulfamethazine in the system. The inhibition of sulfamethazine dissolution was synchronous with the adsorption of benzoic acid on the sulfonamide particles. As low as 5mg. % polyvinylpyrrolidone prevented the adsorption of benzoic acid on sulfamethazine and, consequently, the suppressive effect of benzoic acid on sulfamethazine dissolution was no longer shown.

Due to the adsorption of chloroquine by magnesium trisilicate, both the BP acid absorption test and the rate of hydrochloric acid uptake, as monitored by pH measurements, were significantly reduced. This reduction was dependent on the amount of chloroquine adsorbed, since multilayer adsorption produced relatively more suppressive effects than did monolayer adsorption. The presence of adsorbed chloroquine also decreased the amounts of magnesium released in an acid medium. The inhibition of the antacid property due to chloroquine adsorption may be attributed to the occupation of the reactive sites of the antacid surface by chloroquine and to a reduction of the surface area of the antacid due to flocculation of the particles.

The hyoscyamine contents of four BPC mixtures (containing either belladonna or hyoscyamus tincture) were determined using the acid‐dye technique. A sample size of 10 ml was required. The mean percentage recovery of hyoscyamine ranged from 99.73 to 101.03 from three mixtures; from the magnesium trisilicate and belladonna mixture, it was 94.8. The effects of pH and adsorption on the extraction of the alkaloid‐dye complex from the mixtures examined are discussed.

In systems containing either cellulose acetate butyrate or ethylcellulose, the intrinsic viscosity of the polymer in the appropriate solvent had no effect on the phase type separated. The latter was dependent on the dielectric constant of the nonsolvent added. Nonsolvents possessing relatively high dielectric constants produced a flocculate phase, while either a coacervate or gel was formed after the addition of nonsolvents of lower dielectric constant.