Forecasting the effect of water gastric emptying patterns on model drug release in an in vitro glass-bead flow-through system.

Oral solid dosage forms are most frequently administered with a glass of water which empties from the stomach relatively fast, but with a certain variability in its emptying kinetics. The purpose of this study was thus to simulate different individual water gastric emptying (GE) patterns in an in vitro glass-bead flow-through dissolution system. Further, the effect of GE on the dissolution of model drugs from immediate-release tablets was assessed by determining the amount of dissolved drug in the samples pumped out of the stomach compartment. Additionally, different HCl solutions were used as dissolution media to assess the effect of the variability of pH of the gastric fluid on the dissolution of three model drugs: paracetamol, diclofenac sodium, and dipyridamole. The difference in fast and slow GE kinetics resulted in different dissolution profiles of paracetamol in all studied media. For diclofenac sodium and dipyridamole tablets, the effect of GE kinetics was well observed only in media, where the solubility was not a limiting factor. Therefore, GE kinetics of co-ingested water influences the drug release from immediate-release tablets, however, in certain cases, other parameters influencing drug dissolution can partly or fully hinder the expression of this effect.

The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of Dipyridamole.

OBJECTIVE: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development. METHODS: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model. RESULTS: GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, Cmax, and AUC from the clinical studies. CONCLUSIONS: This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models.

A validated stability-indicating reversed-phase-HPLC method for dipyridamole in the presence of degradation products and its process-related impurities in pharmaceutical dosage forms.

In this study, we developed and validated a method to determine dipyridamole-related impurities in pharmaceutical dosage forms using the reversed-phase-HPLC technique. All impurities were separated on a YMC pack C8 (150 mm × 4.6 mm, 3.0 µm) analytical column using a suitable mobile phase. Mobile phase A was 10 mM concentration of phosphate buffer (pH adjusted to 4.7 by adding diluted orthophosphoric acid) and mobile phase B was buffer:acetonitrile:methanol (at the ratio of 30:40:30 v/v). The optimized chromatographic conditions used in the experiment were as follows: flow rate, 1.0 mL/min; injection volume, 10 µL and column temperature, 35°C. Chromatographic detection was performed at 295 nm. The stressed samples were analyzed for degradation under acidic, basic, peroxide, water hydrolysis, and physical degradation conditions. The proposed method was validated according to International Conference on Harmonization (ICH) guidelines, and found to be specific, linear, accurate and have a robust stability-indicating nature. The method showed excellent linearity from limit of quantification (LOQ) to 150% level of concentrations for all impurities. The correlation coefficient (r2 ) for all impurities was between 0.995 and 0.999. The recovery study was performed from LOQ to 150% level concentrations, with mean recovery values between 92.9% and 103.2%, respectively. The developed method can be used to determine dipyridamole and its relative impurities. The degradation and validated study results indicate its stability-indicating nature. Therefore, the method can be used in pharmaceutical research and development and quality control departments.

[Theophylline adenosine dipyridamole (CTAD) and citrate evaluation to survey unfractionated heparin treatment: a delayed centrifugation validation for anti-Xa measurement?]. / Évaluation du citrate théophylline adénosine dipyridamole (CTAD) et du citrate comme anticoagulant dans la surveillance du traitement par héparine non fractionnée : validation d'une centrifugation différée pour le dosage de l'anti-Xa.

Unfractionated heparin (UFH) is the main anticoagulante used in intensive care unit. The anticoagulant effect is monitored by activated partial thrombin time (aPTT) and anti-Xa activity (anti-Xa) measurement. However, delayed centrifugation induces platelet factor 4 (PF4) release and anti-Xa decrease. Several studies have concluded that aPTT and anti-Xa measurement should be performed within 2 hours in citrated anticoagulant but may be delayed longer in citrate theophylline adenosine and dypiridamol (CTAD) anticoagulant. The objective of this study was to compare the stability of both aPTT and anti-Xa in citrate and CTAD samples, and to determine the effect of delayed centrifugation on both aPTT, anti-Xa results, and PF4 release in citrate samples only. METHODS: aPTT and anti-Xa were measured in citrate and CTAD anticoagulant samples from 93 patients. Delayed centrifugation was performed in citrate samples from 31 additional patients, with hourly aPTT and anti-Xa measurement from 1 to 6 hours. In 14 of these last patients, PF4 release was also evaluated with Human CXCL4/PF4 Quantikine ELISA Kit. RESULTS: We observed a significant correlation between citrate and CTAD anticoagulant for aPTT (r2=0.94) and anti-Xa (r2=0.95). With Bland-Altman correlation, a minor bias was observed for anti-Xa (-0.025±0.041). Delayed centrifugation in citrated anticoagulant showed an excellent concordance from 1 to 4 hours for aPTT (-4.0±5.3 s) and anti-Xa (1.10-9±0.058 UI/mL) measurements. Moreover, PF4 release was not different between 1 hour (31.5±14.7 ng/mL) and 4 hours (33.8±11.8 ng/mL). CONCLUSION: We have demonstrated that anti-Xa measurement for unfractionated heparin should be done 4 hours in citrated plasma and that CTAD was not better than citrate. However, these initial findings require confirmation using other aPTT and calibrated anti-Xa assays.

Kinetic stability of amorphous dipyridamole: A fast scanning calorimetry investigation.

One of the main tasks of modern pharmaceutics is enhancing the solubility of drugs. The approaches for solving this problem include producing active pharmaceutical ingredients in the amorphous state. However, the use of amorphous drugs requires the determination of their kinetic stability. The latter is often assessed using isothermal techniques, which are time-consuming. Alternatively, non-isothermal methods can be employed, allowing to determine the kinetic triplet more rapidly. Also, such techniques can be used to develop predictive models for storage stability. The production of the amorphous state itself typically requires fast cooling rates, which may not be easily accessible. Fast scanning calorimetry is a promising tool for the investigation of amorphous drug systems. In the present work, the crystallization of the model drug dipyridamole was investigated using the fast scanning calorimetry method. The kinetic stability of the amorphous form of the drug was evaluated using both, isothermal and non-isothermal methods. The Nakamura crystallization model was found to be applicable for the prediction of the temporal stability of the amorphous drug forms. The obtained results may find applications in the investigation of the kinetic stability of amorphous drug systems.

Dipyridamole inhibits α-amylase/α-glucosidase at sub-micromolar concentrations; in-vitro, in-vivo and theoretical studies.

Dipyridamole (DP) elevates cyclic Adenosine Monophosphate (cAMP) levels in platelets, erythrocytes, and endothelial cells and also blocks adenosine reuptake. It is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease (CAD). The flexible backbone, hydrophobic nature, and several available hydrogen bond (H-bond) donors and acceptors are well suited structural features of DP for inhibition/activation of enzymes. Substrates of α-amylase (α-Amy) and α-Glucosidase (α-Glu), known as key absorbing enzymes, have functional groups (OH groups) similar to DP. Since hypoglycemia can occur in diabetes disease and there is a significant link between diabetes and cardiovascular diseases (CVD), thus this study aimed to evaluate the inhibitory properties of DP against α-Amy and α-Glu, as enzyme targets of interest under hypoglycemia condition. DP inhibited the α-Glu and α-Amy activity in a dose dependent manner with IC50 values 19.4 ±â€¯0.3 and 30.1 ±â€¯0.4 µM, respectively. Further, the Ki values of DP for α-Glu and α-Amy were determined as 2.9 ±â€¯0.2 and 3.1 ±â€¯0.4 µM in a competitive-mode and mixed-mode inhibition, respectively. Also, DP had binding energies of -7.3 and -6.5 kcal/mol, to communicate with the active site of α-Glu and α-Amy, respectively. In addition, in-vivo studies revealed that the blood glucose concentration diminished after taking of DP compared to positive control group (p < 0.01). Accordingly, the results of the current work may prompt the scientific community to investigate the possible interconnection between DP clinical (side) effects and its α-Glu and α-Amy inhibitory properties.

Calculation of drug-polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations.

Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realize the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realized.

Mechanistic study on hydrodynamics in the mini-scale biphasic dissolution model and its influence on in vitro dissolution and partitioning.

Biphasic dissolution models were proposed to provide good predictive power for in vivo absorption kinetics. However, up to date the impact of hydrodynamics in mini-scale models are not well understood. Consequently, the aim of this work was to investigate different setups of a previously published mini-scale biphasic dissolution model (miBIdi-pH-II) to better understand the relevance of hydrodynamics for evaluating kinetic parameters and to simultaneously increase the robustness of the experimental model. As a first step, the hydrodynamics within the aqueous phase were characterized by in silico simulations of the flow patterns. Different settings, such as higher rotation speeds of the paddles, the implementation of a second propeller into the aqueous phase, and different shapes of aqueous stirrers were investigated. Second, to evaluate the results of the in silico simulations, in vitro experiments with glitter were carried out. Last, the same settings were applied in the miBIdi-pH-II using dipyridamole (DPD) as model compound to estimate kinetic parameters by applying a compartment-based modelling approach. Both in vitro experiments with glitter or DPD demonstrated the adequateness of the previous in silico hydrodynamic simulations. The use of higher rotation speeds and a second aqueous propeller resulted in more homogeneous mixing of the aqueous phase. This resulted in faster distribution of dissolved active pharmaceutical ingredient (API) into the octanol phase. A kinetic model was successfully applied to quantify the influence of hydrodynamics on the partitioning rate of the API into the octanol phase. In conclusion, the combination of in silico and in vitro methods was demonstrated to be powerful for investigating the flow patterns within the miBIdi-pH-II. A comprehensive understanding of the hydrodynamics and the respective influence on the dissolution and apparent partitioning into the octanol phase in the biphasic dissolution model was obtained and completed by using a compartmental kinetic model. This model allowed successful quantification of how the hydrodynamics influence the partitioning of API into the octanol phase.

Tunable Elastomers with an Antithrombotic Component for Cardiovascular Applications.

This study reports the development of a novel family of biodegradable polyurethanes for use as tissue engineered cardiovascular scaffolds or blood-contacting medical devices. Covalent incorporation of the antiplatelet agent dipyridamole into biodegradable polycaprolactone-based polyurethanes yields biocompatible materials with improved thromboresistance and tunable mechanical strength and elasticity. Altering the ratio of the dipyridamole to the diisocyanate linking unit and the polycaprolactone macromer enables control over both the drug content and the polymer cross-link density. Covalent cross-linking in the materials achieves significant elasticity and a tunable range of elastic moduli similar to that of native cardiovascular tissues. Interestingly, the cross-link density of the polyurethanes is inversely related to the elastic modulus, an effect attributed to decreasing crystallinity in the more cross-linked polymers. In vitro characterization shows that the antiplatelet agent is homogeneously distributed in the materials and is released slowly throughout the polymer degradation process. The drug-containing polyurethanes support endothelial cell and vascular smooth muscle cell proliferation, while demonstrating reduced levels of platelet adhesion and activation, supporting their candidacy as promising substrates for cardiovascular tissue engineering.

Application of an In Vitro Dissolution/Permeation System to Early Screening of Oral Formulations of Poorly Soluble, Weakly Basic Drugs Containing an Acidic pH-Modifier.

This study aimed to evaluate the usefulness of the dissolution/permeation system (D/P system) as an in vitro tool for early screening of oral formulations of weakly basic drugs containing an acidic pH-modifier. Dipyridamole, having a prominent pH-dependent solubility, was used as a model drug, and various granules containing different amounts of fumaric acid were prepared. Prepared granules were administered orally to hypochlorhydria model rats. It was confirmed that fumaric acid improved the absorption of dipyridamole depending on its amount in the granules. Separately, dissolution and permeation of dipyridamole were observed in vitro in the D/P system. When using a medium with a low buffer capacity which mimicked the human intestinal fluid, rank order of the permeated amount of dipyridamole from various granules in the D/P system did not correlate with its absorption in hypochlorhydric rats. In contrast, when applying a medium with high buffer capacity, the permeated amount in the D/P system well reflected the effects of fumaric acid on the in vivo absorption of dipyridamole. In conclusion, by setting appropriate experimental protocols according to the properties of test compounds and formulations, D/P system can be a potent in vitro tool to predict in vivo performance of oral formulations.

On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing.

A method for the production of liquid capsules with the potential of modifying drug dose and release is presented. For the first time, the co-ordinated use of fused deposition modelling (FDM), 3D printing and liquid dispensing to fabricate individualised dosage form on demand in a fully automated fashion has been demonstrated. Polymethacrylate shells (Eudragit EPO and RL) for immediate and extended release were fabricated using FDM 3D printing and simultaneously filled using a computer-controlled liquid dispenser loaded with model drug solution (theophylline) or suspension (dipyridamole). The impact of printing modes: simultaneous shell printing and filling (single-phase) or sequential 3D printing of shell bottom, filling and shell cap (multi-phase), nozzle size, syringe volume, and shell structure has been reported. The use of shell thickness of 1.6 mm, and concentric architecture allowed successful containment of liquid core whilst maintaining the release properties of the 3D printed liquid capsule. The linear relationship between the theoretical and the actual volumes from the dispenser reflected its potential for accurate dosing (R2 = 0.9985). Modifying the shell thickness of Eudragit RL capsule allowed a controlled extended drug release without the need for formulation change. Owing to its low cost and versatility, this approach can be adapted to wide spectrum of liquid formulations such as small and large molecule solutions and obviate the need for compatibility with the high temperature of FDM 3D printing process. In a clinical setting, health care staff will be able to instantly manufacture in small volumes liquid capsules with individualised dose contents and release pattern in response to specific patient's needs.

Study of controlled-release floating tablets of dipyridamole using the dry-coated method.

Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80 mg HPMC K4M in the core tablet, 80 mg HPMC E15 in core tablet and 40 mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12 h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8 h.

Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing.

Three dimensional (3D) extrusion-based printing is a paste-based rapid prototyping process, which is capable of building complex 3D structures. The aim of this study was to explore the feasibility of 3D extrusion-based printing as a pharmaceutical manufacture technique for the fabrication of gastro-floating tablets. Novel low-density lattice internal structure gastro-floating tablets of dipyridamole were developed to prolong the gastric residence time in order to improve drug release rate and consequently, improve bioavailability and therapeutic efficacy. Excipients commonly employed in the pharmaceutical study could be efficiently applied in the room temperature 3D extrusion-based printing process. The tablets were designed with three kinds of infill percentage and prepared by hydroxypropyl methylcellulose (HPMC K4M) and hydroxypropyl methylcellulose (HPMC E15) as hydrophilic matrices and microcrystalline cellulose (MCC PH101) as extrusion molding agent. In vitro evaluation of the 3D printed gastro-floating tablets was performed by determining mechanical properties, content uniformity, and weight variation. Furthermore, re-floating ability, floating duration time, and drug release behavior were also evaluated. Dissolution profiles revealed the relationship between infill percentage and drug release behavior. The results of this study revealed the potential of 3D extrusion-based printing to fabricate gastro-floating tablets with more than 8h floating process with traditional pharmaceutical excipients and lattice internal structure design.

Numerical simulation of hot-melt extrusion processes for amorphous solid dispersions using model-based melt viscosity.

Simulation of HME processes is a valuable tool for increased process understanding and ease of scale-up. However, the experimental determination of all required input parameters is tedious, namely the melt rheology of the amorphous solid dispersion (ASD) in question. Hence, a procedure to simplify the application of hot-melt extrusion (HME) simulation for forming amorphous solid dispersions (ASD) is presented. The commercial 1D simulation software Ludovic® was used to conduct (i) simulations using a full experimental data set of all input variables including melt rheology and (ii) simulations using model-based melt viscosity data based on the ASDs glass transition and the physical properties of polymeric matrix only. Both types of HME computation were further compared to experimental HME results. Variation in physical properties (e.g. heat capacity, density) and several process characteristics of HME (residence time distribution, energy consumption) among the simulations and experiments were evaluated. The model-based melt viscosity was calculated by using the glass transition temperature (Tg) of the investigated blend and the melt viscosity of the polymeric matrix by means of a Tg-viscosity correlation. The results of measured melt viscosity and model-based melt viscosity were similar with only few exceptions, leading to similar HME simulation outcomes. At the end, the experimental effort prior to HME simulation could be minimized and the procedure enables a good starting point for rational development of ASDs by means of HME. As model excipients, Vinylpyrrolidone-vinyl acetate copolymer (COP) in combination with various APIs (carbamazepine, dipyridamole, indomethacin, and ibuprofen) or polyethylene glycol (PEG 1500) as plasticizer were used to form the ASDs.

PLLA-PHB fiber membranes obtained by solvent-free electrospinning for short-time drug delivery.

Fibers of poly(L-lactic acid) (PLLA)/polyhydroxybutyrate (PHB) with different concentrations of the drug dipyridamole (DPD) were prepared using solvent-free melt electrospinning to obtain a polymeric drug delivery system. The electrospun fibers were morphologically, structurally, thermally, and dynamically characterized. Crazes that resemble lotus root crevices were interestingly observed in the 7:3 PLLA/PHB fibers with 1% DPD. The crystallinity of PLLA slightly decreased as PHB was incorporated, and the addition of DPD significantly reduced the melting temperature of the composite. The interactions between PLLA and PHB mainly occurred at a proportion of 7:3, and drug encapsulation in the fibers was verified. The kinetic profiles of drug release demonstrated the predominant multiple patterns involving a diffusional stage in the short-term mode of release and kinetic process related to the hydrolysis of the biopolymers. Furthermore, the dynamic behavior of the polymer molecules was evaluated based on the segmental mobility using probe electron spin resonance spectroscopy. The segmental mobility in the amorphous fraction of PLLA decreased with increasing PLLA content. The 9:1 PLLA/PHB system was more resistant to polymer hydrolysis than to the 7:3 system and the rate of diffusion transport was approximately two times higher for the 7:3 PLLA/PHB fibers than for the 9:1 PLLA/PHB fibers.

Understanding the generation and maintenance of supersaturation during the dissolution of amorphous solid dispersions using modulated DSC and 1H NMR.

In this study, the dissolution behaviour of dipyridamole (DPM) and cinnarizine (CNZ) spray-dried amorphous solid dispersions (ASDs) using polyvinyl pyrrolidone (PVP) and polyacrylic acid (PAA) as a carrier matrix were evaluated and compared. The drug concentrations achieved from the dissolution of PVP and PAA solid dispersions were significantly greater than the equilibrium solubility of crystalline DPM and CNZ in phosphate buffer pH 6.8 (PBS 6.8). The maximum drug concentration achieved by dissolution of PVP and PAA solid dispersions did not exceed the theoretically calculated apparent solubility of amorphous DPM and CNZ. However, the degree of supersaturation of DPM and CNZ increased considerably as the polymer weight fraction within the solid dispersion increased. In addition, the supersaturation profile of DPM and CNZ were studied in the presence and absence of the polymers. PAA was found to maintain a higher level of supersaturation compared to PVP. The enhanced drug solution concentration following dissolution of ASDs can be attributed to the reduced crystal growth rates of DPM and CNZ at an equivalent supersaturation. We have also shown that, for drugs having high crystallization tendency and weak drug-polymer interaction, the feasible way to increase dissolution might be increase the polymer weight fraction in the ASD. Solution 1H NMR spectra were used to understand dissolution mechanism and to identify drug-polymer interaction. The change in electron densities of proton attached to different groups in DPM and CNZ suggested drug-polymer interaction in solution. The relative intensities of peak shift and nature of interaction between drug and polymer in different systems are different. These different effects suggest that DPM and CNZ interacts in a different way with PVP and PAA in solution which goes some way towards explaining the different polymeric effect, particularly in terms of inhibition of drug recrystallization and dissolution of DPM and CNZ ASDs. These results established that the different drug/polymer interactions in the solid state and in solution give rise to the variation in dissolution profile observed for different systems.

From benchtop to pilot scale-experimental study and computational assessment of a hot-melt extrusion scale-up of a solid dispersion of dipyridamole and copovidone.

The aim of our work was to study and define a computationally-based adiabatic scale-up methodology for a hot-melt extrusion (HME) process to produce an amorphous solid dispersion (ASD). As a drug product becomes commercially viable, there is a need for scaling up the manufacturing process. In the case of HME used for the formation of ASDs, scale-up can be challenging due to the fundamental differences in how heat is generated in extruders of differing scale, i.e. conduction vs. viscous dissipation and the significant role heat generation plays in determining the final product attributes. Using a 30%w/w dipyridamole-in-copovidone formulation, 11 mm-, 16 mm- and 24 mm-diameter extruders with L/D 40, solid-state characterization tools, a geometric scaling equation, and Ludovic® twin-screw extrusion software, we compared the total imparted material energy, the conducted energy and the difference between barrel and melt temperature at die exit for various feed rates and screw speeds. Numerical simulation identified desirable adiabatic conditions at multiple extruder scales in agreement with the chosen scaling factor. With the use of computational tools, the energetics in an extrusion process can be evaluated and processing conditions can be selected to identify the most efficient scaling of a HME process.

Milk caseins as useful vehicle for delivery of dipyridamole drug.

The interaction of bovine milk α- and ß-caseins as an efficient drug carrier system with Dipyridamole (DIP) was investigated using spectroscopy and molecular docking studies at different temperatures (20-37 °C). FTIR, CD, and fluorescence spectroscopy methods demonstrated that α- and ß-caseins interact with DIP molecule mainly via hydrophobic and hydrophilic interactions and change in secondary structure of α- and ß-caseins. DIP showed a higher quenching efficiency and binding constant of α-casein than ß-casein. There was only one binding site for DIP and it was located on the surface of the protein molecule. The thermodynamic parameters of calculation showed that the binding process occurs spontaneously and demonstrated that α- and ß-caseins provide very good binding and entrapment to DIP via hydrogen bonds, Van der Waals forces, and hydrophobic interactions. Fluorescence resonance energy transfer, synchronous fluorescence spectroscopy, and docking study showed that DIP binds to the Trp residues of α- and ß-casein molecules with short distances. Docking study showed that DIP molecule made several hydrogen bonds and van der Waals interactions with α- and ß-caseins. The study of cell culture and micellar solubility of DIP demonstrated α- and ß-caseins relatively the same helping in delivery of DIP. Milk α- and ß-caseins are considered as a useful vehicle for the solublization and stabilization of DIP in aqueous solution at natural pH.

Stability of Acetazolamide, Baclofen, Dipyridamole, Mebeverine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4.

The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.

Evaluation of CTAD (citrate-theophylline-adenosine-dipyridamole) as a universal anticoagulant in dogs.

CTAD (citrate-theophylline-adenosine-dipyridamole) has been shown to be an almost universal anticoagulant in human and feline medicine, allowing most hematology, coagulation, and biochemical analyses. Forty canine blood specimens were collected in CTAD, EDTA, heparin, and citrate for hematology, biochemistry, and coagulation analyses. CTAD partially limited platelet aggregation observed in EDTA blood smears. CTAD specimens gave similar and well-correlated results for most variables of a complete blood cell count, except for mean corpuscular volume, which was moderately higher, and mean corpuscular hemoglobin concentration, which was moderately lower in CTAD than in EDTA; reticulocyte and platelet indexes were poorly correlated. CTAD plasma gave similar results to citrate for fibrinogen, antithrombin, and D-dimers, and relatively similar results for prothrombin time, but activated partial thromboplastin time was poorly correlated. Triglycerides, cholesterol, glucose, total proteins, phosphate, iron, alanine aminotransferase, γ-glutamyl transferase, and lipase were similar and well correlated in CTAD and heparin plasmas. Urea, creatinine, albumin, alkaline phosphatase, amylase, and aspartate aminotransferase showed moderate-to-marked bias, but these variables could be measured in CTAD plasma if new reference intervals were determined. Creatine kinase activity, potassium, chloride, and total carbon dioxide measurements are not recommended in CTAD plasma. CTAD is a prospective candidate as an almost universal anticoagulant for routine hematology, some plasma coagulation, and many biochemistry variables in dogs. Definitive recommendations will require study of abnormal canine blood specimens.