Stability of Olmesartan Medoxomil Extemporaneous Suspensions.

Background: Olmesartan medoxomil (OLM) is only available in the United States as tablets. The United States Pharmacopoeia (USP) has placed OLM on its priority list of preparations that require stability data to support practitioner compounding. Objective: The purpose of the study was to develop a stability-indicating assay and then determine the beyond-use date (BUD) for an extemporaneous OLM suspension. Methods: A reverse-phase high-performance liquid chromatography (HPLC) assay was developed and validated according to guidelines for USP official compounded monographs. OLM 2 mg/mL suspensions were compounded with Ora-Sweet and Ora-Plus and stored at room temperature or in a refrigerator. Suspensions were assayed periodically over 90 days for OLM concentration and observed for physical stability. The pH was measured at the beginning and end of the study. Results: The OLM concentration remained above 97% of the starting concentration for 90 days when stored in the refrigerator and above 94% of the starting concentration for 90 days when stored at room temperature. The suspension pH did not change and indicators of physical stability were unchanged for 90 days. Conclusion: OLM 2 mg/mL suspensions were chemically and physically stable at room temperature and in the refrigerator for 90 days. The BUD may be set at 90 days under either storage condition.

Stability and Beyond-Use Date of a Compounded Thioguanine Suspension.

Background: Thioguanine (TG) is available only in the form of 40 mg tablets in the United States, and the patient population in which TG is used comprises mostly children. Recognizing its importance as a therapeutic agent and limited stability data for its compounded preparation, the United States Pharmacopoeia has listed TG in its priority list of compounded preparations monographs. Objective: The goal of the present study was to generate stability data and establish a beyond-use date for compounded TG suspension. Methods: Suspensions were compounded using TG tablets and ORA-Plus and ORA-Sweet as vehicles. A robust high-performance liquid chromatography method was developed and validated. TG and guanine (G) in suspensions were quantified immediately after compounding and at regular intervals for 90 days. Physical stability of suspensions was evaluated by observation of organoleptic properties. Results: Results from the study indicate that average TG levels in suspensions remained above 90% of the starting concentration and G formation was less than 2.5% for 90 days. There was no statistically significant difference in the amount of TG degraded over 90 days between suspensions stored at room temperature and in refrigerated conditions. There was also no statistically significant difference in G concentration of suspensions between day 0 and day 90. Conclusion: TG suspensions are stable for 90 days when stored at room temperature or refrigerated conditions and the beyond-use date can be set to 90 days.

Kinetics of Tetracaine Solvolysis in Propylene Glycol.

Tetracaine is a potent ester-type local anesthetic. Recent publications describe the use of TC free base in topical anesthetic formulations containing propylene glycol. While solvolysis of tetracaine in propylene glycol solutions has been reported, there are no detailed reports on the kinetics of tetracaine reaction with propylene glycol. The objectives of the study were to characterize the kinetics and temperature dependence of tetracaine solvolysis in PG solutions. In this study, products of tetracaine degradation in propylene glycol solution at 60°C were collected and analyzed by high-performance liquid chromatographymass spectrometry and nuclear magnetic resonance. The kinetics of tetracaine reaction with propylene glycol was studied at 22°C, 30°C, 40°C, and 60°C. The reaction of tetracaine with n-propanol and isopropanol was also studied. Analysis was performed by high-performance liquid chromatography-mass spectrometry with ultraviolet detection using a gradient elution method. Tetracaine concentrations were quantitated using a four-point standard curve. Tetracaine degradation rates were consistent with apparent first order kinetics at all temperatures studied. The data indicated that tetracaine degrades via transesterification with propylene glycol. The rate constants ranged from 2.26 x 10-3 d-1 at 22°C to 7.06 x 10-2 d-1 at 60°C. Arrhenius analysis indicated an activation energy for the reaction of 74.1 kJ/mol, which is similar to published values for the hydrolysis of pharmaceutical esters.

The use of extemporaneously compounded 1% tetracaine to improve adherence with clotrimazole 1% topical solution in the treatment of ear infection: a case report.

For most medically amenable conditions, adherence to drug therapy is a necessary condition for a successful outcome. Drug side effects, especially pain, can interfere with the desired outcome. We report a case of non-adherence due to severe pain associated with the topical use of clotrimazole 1% solution in the ear. Instillation of tetracaine 1% solution prior to the administration of the clotrimazole blocked the pain sensation allowing the patient to successfully complete the antifungal therapy.

Assessment of the accuracy of pharmacy students' compounded solutions using vapor pressure osmometry.

OBJECTIVE. To assess the effectiveness of using a vapor pressure osmometer to measure the accuracy of pharmacy students' compounding skills. DESIGN. Students calculated the theoretical osmotic pressure (mmol/kg) of a solution as a pre-laboratory exercise, compared their calculations with actual values, and then attempted to determine the cause of any errors found. ASSESSMENT. After the introduction of the vapor pressure osmometer, the first-time pass rate for solution compounding has varied from 85% to 100%. Approximately 85% of students surveyed reported that the instrument was valuable as a teaching tool because it objectively assessed their work and provided immediate formative assessment. CONCLUSIONS. This simple technique of measuring compounding accuracy using a vapor pressure osmometer allowed students to see the importance of quality control and assessment in practice for both pharmacists and technicians.

Stability of non-aqueous topical tetracaine and clotrimazole solutions in polypropylene droptainer bottles.

Tetracaine topical solution may improve patient adherence with topical clotrimazole therapy for fungal otitis externa. The chemical stability of tetracaine 1% and combination clotrimazole 1% with tetracaine 1% topical solutions was determined using a stability-indicating high-performance liquid chromatography assay. Propylene glycol and polyethylene glycol 400 were used as anhydrous solvents. Standard curves for tetracaine and clotrimazole were linear with r2 > or = 0.999. Clotrimazole did not degrade in either propylene glycol or polyethylene glycol 400 throughout the 90-day study period. Tetracaine degraded significantly in propylene glycol but not in polyethylene glycol 400. A beyond-use date of 90 days is supported for tetracaine and the combination clotrimazole-tetracaine solution in polyethylene glycol 400. A beyond-use date of 60 days is supported for tetracaine and the combination clotrimazole-tetracaine in propylene glycol.

Calcium alginate nanoparticles synthesized through a novel interfacial cross-linking method as a potential protein drug delivery system.

The goal of this research work was to develop a novel technique to synthesize calcium alginate nanoparticles using pharmaceutically relevant microemulsions. Stable microemulsion-based reactors were prepared using aqueous sodium alginate, aqueous calcium chloride, dioctyl sodium sulfosuccinate (DOSS), and isopropyl myristate. The reactor microemulsions were characterized via conductivity and dynamic light scattering (DLS) experiments. The conductivity data indicated composition- and reagent-dependent variations in electrical conductivity when the aqueous phase containing reagents were present at or above a Wo (Wo = [DOSS]/[water]) value of 14. The reactor microemulsions were of approximately 6 nm sized droplets. When the reactor microemulsions were mixed and sonicated for 1 h approximately, 350-nm-sized calcium alginate nanoparticles were produced, as indicated by DLS measurements. The particles were isolated and characterized via low-vacuum scanning electron microscopy. The electron micrographs corroborate the DLS results. The nanoparticles were evaluated as a drug delivery system by incorporating bovine serum albumin (BSA) and performing in vitro release and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies. The BSA release profile was characterized by an initial burst release followed by a sustained-release phase. SDS-PAGE studies indicated that the incorporated protein did not suffer covalent aggregation or degradation via fragmentation.

Physicochemical and binder properties of starch obtained from Cyperus esculentus.

The purpose of this study was to isolate starch from the tubers of Cyperus esculentus L. and evaluate its physicochemical and binder properties. Extraction of starch using sodium metabisulfite yielded 37 g of starch per 100 g of the tubers. Scanning electron microscopy indicated that Cyperus starch consists of oval to elliptical particles with a smooth surface. Cyperus starch demonstrates a narrow particle size distribution with a mean of 8.25 µm. Cyperus starch conforms well to United States Pharmacopeia standards established for widely used starches like maize and potato. The X-ray powder diffraction pattern and moisture sorption profile of Cyperus starch were comparable to that of maize starch. Cyperus starch had lower swelling power than maize and potato starch, indicative of stronger associative forces within the granules. Carr's index and Hausner ratio indicate that Cyperus starch should have comparable flow properties with respect to maize and potato starch. Cyperus starch was employed as binder for the formulation of metronidazole tablets. Formulations containing 5%, 7.5%, and 10% Cyperus starch were compared with those containing 10% potato starch. At 10% binder concentration, the tablets containing Cyperus starch exhibited better hardness and negligible friability as compared with those with potato starch. Although the binder concentration had a significant effect on the disintegration time of the tablets, it did not seem to affect the dissolution profile. These results indicate that Cyperus starch provides excellent binding properties without compromising drug release characteristics and should be explored in pharmaceutical formulations.

Stability of sodium bicarbonate solutions in polyolefin bags.

PURPOSE: The stability of sodium bicarbonate solutions in sterile water for injection or 5% dextrose injection stored at 21-24 degrees C or 2-4 degrees C was evaluated. METHODS: Sodium bicarbonate injection was obtained in 50-mL vials of 8.4% (1 meq/mL). A total of 50, 100, or 150 meq of sodium bicarbonate was added to each 1-L polyolefin bag of either sterile water for injection or 5% dextrose injection. All solutions were prepared in a laminar-airflow hood using aseptic technique. Bags were punctured once to remove headspace air and once for the addition of each 50 meq of sodium bicarbonate. Six replicates of each test solution were prepared. The solutions were stored at 21-24 degrees C and 2-4 degrees C. Control solutions (50 and 150 meq) were similarly prepared in triplicate. Control solutions were sparged with either nitrogen gas or oxygen gas before storage. Sodium bicarbonate stability was assessed by measuring solution pH. Bicarbonate content was measured utilizing titration. Both pH and bicarbonate concentrations were measured immediately upon preparation and on days 3, 5, and 7 for both test and control solutions. RESULTS: All 95% confidence interval values for sample solution pH remained within 7.0-8.5 for seven days at 2-4 degrees C. CONCLUSION: Sodium bicarbonate solutions of 50, 100, and 150 meq in sterile water for injection or 5% dextrose injection were stable for up to seven days when refrigerated. The 50-meq solution was stable for up to 48 hours when stored at room temperature, and the 100- and 150-meq solutions were stable for up to 30 hours when stored at room temperature.

Solid-state stability and characterization of hot-melt extruded poly(ethylene oxide) films.

Poly(ethylene oxide) (PEO) was used to prepare thin polymer films containing clotrimazole (CT) utilizing hot-melt extrusion (HME) technology. Films containing PEOs of two different molecular weights and the drug were investigated for solid-state characteristics, moisture-sorption, bioadhesivity, mechanical properties, release characteristics, and physical and chemical stability of the drug within the HME films. The solid-state characterization of the drug and the polymer were performed utilizing differential scanning calorimetry and X-ray diffractometry. A Texture analyzer was utilized to study the bioadhesive and mechanical properties of the HME films. Physical and chemical stability of the films, stored at 25 degrees C/60% RH, was studied for up to 12 months. XRD profiles indicated that the drug was physically unstable (recrystallization of the drug occurred) after storage for 3 months at 25 degrees C/60% RH. Based on the DSC studies, it has been proposed that the recrystallization of the drug may be due to the folding (due to HME) and unfolding (upon storage) of the linear PEO chains. Desirable bioadhesive, mechanical, and thermoplastic properties of PEO qualify it as a promising and potential drug carrier. However, further investigation is necessary to enhance the physical stability of these PEO-drug systems.

The relationship between surface adsorption and the hydrolysis of amitraz in anionic surfactant solutions.

The adsorption of amitraz to various adsorbents was studied in terms of the amount and rate of adsorption and the effect that adsorption had on the stability of amitraz in an aqueous environment. Adsorption results showed that in terms of their ability to adsorb amitraz from solution the adsorbents tested in this study can be ordered as follows: coarse carbon > cation exchange resin > or = anion exchange resin > fine carbon. Amitraz was not adsorbed on sand and potassium oxihumate. Adding sodium lauryl sulfate and potassium oxihumate to aqueous suspensions of suspended adsorbents containing adsorbed amitraz showed that both these anionic surfactants significantly increased the hydrolysis rate because the half-lives for amitraz was reduced from 27 days for a suspension to only 8 hours for amitraz adsorbed to a cation exchange resin and suspended in an aqueous buffer pH 5.8 containing 0.5% of the anionic surfactant sodium lauryl sulfate and 12 hours when 1% potassium oxihumate was added.

IPM/DOSS/water microemulsions as reactors for silver sulfadiazine nanocrystal synthesis.

The first goal of this work was the preparation of a water-in-oil microemulsion from components generally regarded as safe for use in humans. Stable formulations without need of a co-surfactant were prepared from isopropyl myristate (IPM), dioctyl sodium sulfosuccinate (DOSS), and water. A ternary phase diagram was prepared for the IPM/DOSS/water system. The IPM/DOSS/water microemulsions were characterized by conductivity and dynamic laser light scattering (DLS). The results obtained from conductivity experiments indicate conductivity values of less than 1 muS/cm and were consistent with the formation of w/o microemulsions. The DLS results showed that the emulsified water droplets had an average diameter range of 9.2 to 19.7 nm, depending on composition. Modulation of the droplet size is possible by varying the water to DOSS molar ratio and DOSS to IPM ratio. The second goal of this work was the preparation of silver sulfadiazine (AgSD) nanoparticles. It was hypothesized that two separate microemulsions containing dispersed aqueous droplets of either sodium sulfadiazine or silver nitrate would react when mixed. The DLS results are consistent with the successful formation of submicron AgSD crystals.

Structural characterization, physicochemical properties, suspension stability, and adsorption properties of four solid forms of amitraz.

This paper reports the identification and preparation of three crystalline (A-C) and one metastable form (D) of amitraz. These were identified by their crystal morphology, crystal structures, aqueous solubility, and thermal properties. Form C was the least soluble (7 mug/mL) and had the highest melting point (115 degrees C). The differences in melting point (82 vs 72 degrees C) and solubility (20 vs 23 mug/mL) of forms A and B were not significant. The metastable noncrystalline form D (Tg = 38 degrees C, transition temperature = 62 degrees C, and melting point = 78 degrees C) was obtained by deposition on the surface of activated carbon from acetonitrile solutions. When the anionic surfactant sodium lauryl sulfate was added to the solubility medium, the solubilities of forms A and B were increased 10-11-fold and that of form C was increased 28-fold. Changing the crystal form had an effect on the stability of amitraz suspensions. Form C was the most stable with a t(1/2) of 136 days, and form B was the least stable with a t(1/2) of 28 days. The stability correlated with solubility differences. The addition of sodium lauryl sulfate to the suspensions increased the rate of hydrolysis (mean t(1/2) = 17 h), and because of increased solubility, there was no difference in the stability of the crystal forms in the anionic surfactant solution.

Water vapor sorption of hot-melt extruded hydroxypropyl cellulose films: effect on physico-mechanical properties, release characteristics, and stability.

Hot-melt extrusion technology was used to prepare thin polymer films containing hydroxypropyl cellulose and clotrimazole (CT). Films containing hydroxypropyl celluloses of different molecular weight and the drug were investigated for moisture-sorption, mechanical properties, and release characteristics. Stability of the films was also studied at 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH for up to 3 months. To study the moisture-sorption of the hot-melt extruded films, a rapid dynamic vapor sorption technique was used. Mechanical properties were evaluated using the Texture Analyzer. The molecular weight of the polymer had a significant effect on the mechanical and release characteristics of the films but did not influence the equilibrium moisture content in the films stored at RHs ranging from 0 to 90%. However, the time to reach equilibrium was longer for the higher molecular weight polymers. The drug release rate was dependent on the rate of erosion, which in turn depended on the molecular weight of the polymer. The films were stable at 25 degrees C/60% RH for up to 3 months with no significant degradation or recrystallization of CT. However, recrystallization of the drug was observed within the films stored in accelerated stability conditions at the end of 3 months in which only 92.9% (+/-1.9) CT remained.

Influence of moisture on the crystal forms of niclosamide obtained from acetone and ethyl acetate.

The purpose of this study was to elucidate the formation of crystal hydrates of niclosamide and to delineate the effect of relative humidity on the crystal forms obtained from acetone and ethyl acetate. Recrystallization of niclosamide was performed in the presence and absence of moisture. Two hydrates and their corresponding anhydrates were isolated. The hydrates obtained by the process of recrystallization from acetone (Form I) and that obtained from ethyl acetate (Form II) were classified based on differences in their dehydration profile, crystal structure, shape, and morphology. Crystals obtained in the absence of moisture were unstable, and when exposed to the laboratory atmosphere transformed to their corresponding hydrates. Differential scanning calorimetry thermograms indicate that Form I changes to an anhydrate at temperatures below 100 degrees C, while Form II dehydrates in a stepwise manner above 140 degrees C. This finding was further confirmed by thermogravimetric analysis. Dehydration of Form II was accompanied by a loss of structural integrity, demonstrating that water molecules play an important role in maintaining its crystal structure. Form I, Form II, and the anhydrate of Form II showed no significant moisture sorption over the entire range of relative humidity. Although the anhydrate of Form I did not show any moisture uptake at low humidity, it converted to the monohydrate at elevated relative humidity (>95%). All forms could be interconverted depending on the solvent and humidity conditions.

Water distribution studies within microcrystalline cellulose and chitosan using differential scanning calorimetry and dynamic vapor sorption analysis.

The objective of the study was to assess and compare the interaction and distribution of water within microcrystalline cellulose (MCC) and chitosan by differential scanning calorimetry (DSC) and dynamic vapor sorption analysis. The amounts of nonfreezing and freezing water in hydrated samples were determined from melting endotherms obtained by DSC. After accounting for the percent crystallinity of MCC and chitosan, no statistically significant difference was observed in their ability to bind water molecules per repeating unit at the minimum water content at which freezing water is evident. Exposure of chitosan to water for 30 min was sufficient to achieve equilibration at 61% w/w actual water content. The moisture sorption profiles were analyzed according to the GAB and Young and Nelson equations. The adsorbed monolayer, externally adsorbed moisture, and internally absorbed moisture were not statistically different for MCC and chitosan after accounting for the amorphous content of the polymers. These studies suggest that chitosan can act as a "molecular sponge," and thus aid in the production of beads by extrusion and spheronization.

Studies on the interaction of water with ethylcellulose: effect of polymer particle size.

The purpose of this research was to investigate the interaction of water with ethylcellulose samples and assess the effect of particle size on the interaction. The distribution of water within coarse particle ethylcellulose (CPEC; average particle size 310 micro m) and fine particle ethylcellulose (FPEC; average particle size 9.7 micro m) of 7 cps viscosity grade was assessed by differential scanning calorimetry (DSC) and dynamic vapor sorption analysis. The amounts of nonfreezing and freezing water in hydrated samples were determined from melting endotherms obtained by DSC. An increase in water content resulted in an increase in the enthalpy of fusion of water for the two particle size fractions of EC. The amount of nonfreezable water was not affected by the change in particle size at low water contents. Exposure of ethylcellulose to water for 30 minutes is sufficient to achieve equilibration within the hydrated polymer at 47% wt/wt water content. The moisture sorption profiles were analyzed according to the Guggenheim-Anderson-de Boer (GAB) and Young and Nelson equations, which can help to distinguish moisture distribution in different physical forms. The amount of externally adsorbed moisture was greater in the case of FPEC. Internally absorbed moisture was evident only with the CPEC. In light of these results, an explanation is offered for the success of FPEC in wet-granulation methods where CPEC was not successful.