Hassan Almoazen

Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH

No HeadingPurpose.To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate.Methods.pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs.Results.pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2–5 is attributed to its higher solubility product (Ksp) than that of the hydrochloride salt. The pH-solubility profiles indicated a pHmax (pH of maximum solubility) of ∼5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts.Conclusions.Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.

A Novel Topical Rapamycin Cream for the Treatment of Facial Angiofibromas in Tuberous Sclerosis Complex

Facial angiofibromas are dermatological manifestations of tuberous sclerosis complex, a neurocutaneous disorder characterized by excess cell growth and proliferation. Oral rapamycin has been used to treat visceral tuberous sclerosis–related tumors; however, the side effect profile of this medicine precludes its routine use in patients lacking significant internal involvement. The authors formulated a novel rapamycin cream that is easy to compound and apply, does not cause local or systemic side effects, and results in a dramatic improvement of facial angiofibromas.

Evaluation of chlorpheniramine maleate microparticles in orally disintegrating film and orally disintegrating tablet for pediatrics

Abstract Objective: To mask the bitterness of Chlorpheniramine Maleate via encapsulating drug into Eudragit EPO microparticles, and then incorporate these microparticles into orally disintegrating films (ODF) and orally disintegrating tablets (ODT) for pediatric uses. Methods: Spray drying of water-in-oil emulsion was utilized to encapsulate Chlorpheniramine Maleate into Eudragit EPO microparticles. Based on an orthogonal experimental design L9 (33), polynomial regression models were developed to evaluate correlation between microparticle properties (encapsulation efficiency and drug release) and variables (X1: weight ratio of polymer to drug, X2: volume ratio of oil to water and X3: Q-flow of spray dryer). ODF and ODT formulations were evaluated including weight variation, content uniformity, tensile strength, disintegration time, friability and dissolution profiles. The bitterness taste test was evaluated in 10 adult volunteers. Results and discussion: From polynomial regression analysis, the best values of variables leading to the optimized microparticles were X1 = 10, X2 = 3 and X3 = 45. The optimized microparticles were incorporated into ODF and ODT with satisfactory weight and drug content uniformity, and acceptable physical strength. Both dosage forms disintegrated immediately (less than 40 s) in simulated saliva solutions. The outcome of taste-masking test indicated that microparticles alleviated drug bitterness significantly; bitterness was not discernible with microparticles incorporated in ODT, whereas only slight bitterness was detected from microparticles incorporated into ODF. Conclusion: Both ODF and ODT are shown to be suitable vehicles for taste masked Chlorpheniramine Maleate microparticles with potential for pediatric uses.

Development of a taste-masked oral suspension of clindamycin HCl using ion exchange resin Amberlite IRP 69 for use in pediatrics

Abstract Purpose: The purpose of this study is to develop an oral suspension of clindamycin resin complex for the potential use in pediatrics. Methods: Several types of Ion exchange resins were screened for their binding efficiency with clindamycin. In order to develop a suspension formulation, several thickening agents, surfactants, sweeting, and flavoring agents were evaluated for their influence on the release of clindamycin from resinate. Rheological studies were also conducted to select the optimum amounts of the suspending agents. The release profiles of clindamycin in SGF and SIF were also evaluated from freshly prepared suspension and from suspension formulation after storage for 1 month at 25 °C and 40 °C. Clindamycin bitterness threshold was determined based on volunteers’ evaluation, and taste evaluation was conducted in 12 adult volunteers who evaluated the taste of the optimized suspension against clindamycin solution. Results: Among all resins tested, Amberlite IRP 69 showed the highest binding efficiency to clindamycin. Several excipients were selected into the suspension formulation based on no or minimum influence on the release of clindamycin from the resinate complex. Moreover, xanthan gum was selected as the optimal suspending agent for the suspension. Clindamycin release profiles in SGF or SIF showed 90% release within 30 min from freshly prepared sample. Clindamycin exhibited good stability profiles at 25 °C and 40 °C over 1 month storage. The mean bitterness threshold of clindamycin was 12.5 μg/ml, and taste evaluation study in adults showed sustainable taste improvement for suspension over clindamycin solution. Conclusion: Clindamycin/resin complexation has shown to be an efficient method to mask the taste of clindamycin and was developed into a suspension formulation that can be used in pediatrics.

Development and physicochemical characterization of clindamycin resinate for taste masking in pediatrics

Abstract Purpose: To evaluate the physicochemical characteristics of clindamycin HCl in a complex form (resinate) with ion exchange resin (IER) (Amberlite IRP69). Methods: Drug–resin complex was prepared by simple aqueous binding method. Drug binding study was carried out at different drug and resin concentrations. Several physicochemical characterization studies were conducted to evaluate the resinate complex. These studies included flow properties, in vitro drug release in SGF and SIF, DSC, TGA, mass spectroscopy and XPRD evaluations. In addition, stability study of resinate complex was conducted at 25 and 40 °C for up to 1 month. Results: Clindamycin and Amberlite IRP69 have formed a complex (resinate) and have shown good flow properties, good thermal properties and chemical stability (short term over 4 weeks) at 25 and 40 °C. Clindamycin release profiles from resinate in SGF and SIF have shown immediate release characteristics and release in simulated saliva has shown dependence on water volume. Conclusion: The clindamycin stable complex with IER (Amberlite IRP69) has the potential for further development as a compatible pediatric liquid formulation (suspension) or a fast disintegrating tablet.

Development of W/O Microemulsion for Transdermal Delivery of Iodide Ions

The objective of this study was to develop a water-in-oil (w/o) microemulsion which can be utilized as a transdermal delivery for iodide ions. Several w/o microemulsion formulations were prepared utilizing Span 20, ethanol, Capryol 90®, and water. The selected formulations had 5%, 10%, 15%, 20%, and a maximum of 23% w/w water content. Potassium iodide (KI) was incorporated in all formulations at 5% w/v. Physicochemical characterizations were conducted to evaluate the structure and stability. These studies included: mean droplet size, pH, viscosity, conductivity, and chemical stability tests. In vitro human skin permeation studies were conducted to evaluate the diffusion of the iodide ion through human skin. The w/o microemulsion formulations were stable and compatible with iodide ions with water content ranging from 5% to 23% w/w. The addition of KI influenced the physicochemical properties of microemulsion as compared to blank microemulsion formulations. In vitro human skin permeation studies indicated that selected formulations improved iodide ion diffusion significantly as compared to control (KI solution; P value < 0.05). Iodide ions were entrapped within the aqueous core of w/o microemulsion. Span 20, ethanol and Capryol 90 protected the iodide ions against oxidation and formed a stable microemulsion. It is worth to note that according to Hofmeister series, iodide ions tend to lower the interfacial tension between water and oil and consequently enhance overall stability. This work illustrates that microemulsion system can be utilized as a vehicle for the transdermal administration of iodide.

Determining the Critical Micelle Concentration in O/W Emulsion Using the Rate Constant of Hydrolysis for Benzyl Acetate

An attempt to evaluate the kinetically effective critical micelle concentration CMC of sodium dodecyl sulfate (SDS) in micellar solutions and in O/W emulsions at 40°C and pH 9 utilizing the pseudo first order rate constant of benzyl acetate hydrolysis was implemented. The critical micelle concentration of SDS in micellar solutions was determined by both surface tension measurements utilizing Wilhelmy plate technique and by rate constant of hydrolysis. Hydrolysis reaction of benzyl acetate was monitored in surfactant solutions as well as in o/w emulsions as a function of time. Emulsion droplets were controlled using microfluidizer 110 T and oily droplets were separated from the emulsion by ultracentrifugation at (11,500 rpm or 9,800 g) prior to analysis by high performance liquid chromatography. The value of the critical micelle concentration (CMC) in micellar solutions in the presence of benzyl acetate as determined from the Wilhelmy plate technique was 7.8 × 10−4 moles/L (CMC in micellar solution was 10 times lower than the value in literature due to use of buffer) while the CMC as determined from the kinetic study was 8.8 × 10−4 moles/L. In emulsion systems, using 5% mineral oil, the CMC value was 8.6 × 10−3 moles/L and at 10% oil, the value doubled to 1.73 × 10−2 moles/L. The above results indicate that kinetics can be used to determine CMC in micellar solutions and in o/w emulsions.

The influence of sodium salts (iodide, chloride and sulfate) on the formation efficiency of sulfamerazine nanocrystals.

Abstract Objective: The purpose of this study is to evaluate the influence of sodium iodide, sodium chloride and sodium sulfate on the formation efficiency of sulfamerazine nanocrystals by wet ball milling. Methods: Sulfamerazine was milled using zirconium oxide beads in a solution containing polyvinylpyrrolidone (PVP) and a sodium salt (iodide, chloride or sulfate). Particle size distributions were evaluated by light diffraction before and after milling. High-performance liquid chromatography was utilized to determine the amount of PVP adsorbed onto sulfamerazine surface. Lyophilized nanocrystals were further characterized by differential scanning calorimetry and dissolution testing. Results: Sulfate ion had more profound effect on reducing particle size via milling than iodide or chloride. We linked our findings to Hofmeister ion series, which indicates that sulfate ions tends to break the water structure, increases the surface tension and lowers the solubility of hydrocarbons in water. We hypothesized that the addition of sulfate ions dehydrated the PVP molecules and enhanced its adsorption onto the sulfamerazine particle surfaces. Consequently, the adsorbed PVP helped to stabilize of the nanosuspension. The nanocrystals that were obtained from the lyophilized milled suspensions exhibited a notable increase in dissolution rate. Conclusion: The addition of sodium sulfate enhanced the formation efficiency of sulfamerazine nanocrystals.

Development of a fast dissolving film of epinephrine hydrochloride as a potential anaphylactic treatment for pediatrics

Abstract Objective: To develop a fast dissolving film strip containing epinephrine HCl for the potential treatment of pediatric anaphylaxis. Methods: Four different films have been prepared by solvent casting technique where the percentages of the polymer (Lycoat RS720) were optimized. The polymer percentages were (20%, 25%, 27% and 30%) of the total formulation weighs. The thickness and elastic modulus of the optimized film was evaluated using dynamic mechanical analyzer. Epinephrine content uniformity was assessed using UV at wavelength 280 nm. For the dissolution test, fast dissolving films (FDFs) were evaluated in 500 Simulated Saliva, with 50 rpm. In vivo taste and disintegration evaluation was performed on six healthy volunteers. Results: Films formed by formulations 1, 2 and 3 were too sticky after drying, while formulation 4 that has 30% polymer content formed smooth, transparent, flexible and uniform film, and therefore, it was selected for further testing. The value of elastic modulus was determined at 1.325 MPa. The thickness of the film at different locations was measured at 0.29 mm. Drug content in film was measured at 93% ±10. More than 90% of epinephrine was released from the film within 7.2 min. Bitterness of epinephrine was masked efficiently according to volunteer’s comments with average disintegration time of 20 s. Conclusion: This study presents potential proof for using FDFs as a replacement therapy of epinephrine injections for pediatrics.

Why analytical testing is needed in pharmaceutical compounding

To the Editor. Oftentimes as educators, we wonder what impact we have on our students. Through our passion and enthusiasm to inspire students to learn, we still ask ourselves, ‘‘Do they learn from our instruction and put into practice lessons learned during their days in the pharmacy program?’’ We periodically evaluate their understanding of lessons through examinations, but we know (as we were once students) that much of the information that was ‘‘crammed’’ is lost after the examination. My phrase for this process is ‘‘bulimic learning.’’ Additionally, we hope that during the introductory pharmacy practice experiences (IPPEs) and the advanced pharmacy practice experiences (APPEs) students will demonstrate that they know and can utilize the lessons learned for the benefit of the patients, consumers, and allied health care professionals they serve. In addition to students assimilating knowledge, we ask ourselves if we have inculcated in them the performancebased skills (eg, communication, problem solving, decision making, and societal responsibility) necessary to navigate the profession effectively and successfully. After all, part of our purpose as educators is to help our students create their professional futures. Fifteen years ago, I stood before my first class of pharmacy students at Ohio Northern University (ONU). My new teaching assignment was to instruct the students in the pathophysiology and pharmacological management of myocardial infarction (MI). I knew this content with the therapeutics sequence would be difficult and not one which every student would embrace. Indeed, I told myself in all likelihood perhaps only a few students would remember what I taught. To facilitate student learning, I developed a mnemonic device for them. Since then, I have tweaked my MI instructional plan based in part on constructive criticisms from students and incorporated new information, but I have always wondered about its value. What follows is a letter I recently received from an alumnus from that first class: Dear Dr. Sprague: I want to take an opportunity to praise ONU College of Pharmacy for the wonderful education I received. It has served me well in my professional career and most recently in my personal life. As I have been telling my story, I find myself referencing my education and specifically your cardiology class and needed to let you know what an impact it has made. As pharmacists, we are trained to serve our patients to extend and save their lives. . .I never dreamed it would be my own. Seven months ago, at the age of 35, I had a heart attack while home with my two small children. It was acute, painful, frightening, and nothing I had ever felt before. I had some classic as well as atypical symptoms and at the time could not process what was happening. My husband arrived and called 911 after explaining how my chest pain and shortness of breath were not subsiding. The medics immediately treated me as a cardiac patient even though I did not ‘‘look the part.’’ I followed everything they said, giving [me] baby aspirin and oxygen. Once en route to the hospital, with the pain level still high, the medic gave me a nitroglycerin; almost immediately the pain reduced although it did not completely subside. At that moment, I knew it was my heart. At the local hospital, I was treated again as a cardiac patient and stabilized. I was being observed and waiting on my 2nd lab draw. The ER physician was surprised to see that, though all my other labs were normal, my troponin had elevated. This marker is something I recalled specifically learning from your cardiology class. It was something you stressed we needed to comprehend when we reviewed the MI process. The physician was surprised that I knew what this meant. I explained I was a pharmacist and confident in knowing what this could indicate. At the heart hospital, I was told by several people that I ‘‘did not look the part.’’ I was told there could be a lab error, but they would continue to draw labs and followup in the morning. Throughout the night, I would ask anurse aboutmy troponin levels.By morning I hada total of 4 results, all increasing with time. I wrote them down and tracked it. I needed to know, did I have a heart attack? The rounding cardiologist asked me to explain my symptoms; after detailing every sensation. I finally said ‘‘I felt like I was having a heart attack.’’ I figured I would make it as clear as possible. He said he doubted it and went on to explain stress and panic attacks. I then inquired about my troponin levels. I explained they had increased. He said ‘‘I will be right back. . .’’ He came back a few minutes later. ‘‘You’re having a cardiac cath!’’ I was taken aback by 2 things, the cath and the fact that I may have possibly been discharged if I had not inquired. The cath was scheduled for the next day—again, because I did not ‘‘look the part.’’ I spoke with another cardiologist the next day, again same scenario, I had to inquire about my troponin levels. He ruffled through some paperwork and then started to explain. My husband and I stopped him. We will wait for the cath results. The cath results: right coronary artery aneurysm with a 90%-95% stenosis beyond with a possible dissection. Open heart surgery to perform CABG the next day. After open heart surgery, I endured several weeks of home nursing and physical therapy and eventually cardiac rehab. It took me 14 weeks to complete rehab; along the way, people would say ‘‘How did you know something was wrong?’’ ‘‘What did it feel like?’’ ‘‘How did you know to ask and inquire about cardiac markers?’’ ‘‘Most people have no idea what troponin American Journal of Pharmaceutical Education 2010; 74 (2) Article 32.