Spray drying Eudragit® E-PO with acetaminophen using 2- and 3-fluid nozzles for taste masking.

Conventional spray drying using a 2-fluid nozzle forms matrix microparticles, where drug is distributed throughout the particle and may not effectively mask taste. In contrast, spray drying using a 3-fluid nozzle has been reported to encapsulate material. The objective of this study was to spray dry Eudragit® E-PO (EE) with acetaminophen (APAP), a water-soluble model drug with a bitter taste, using 2- and 3-fluid nozzles for taste masking. Spray drying EE with APAP, however, resulted in yields of ≤ 13 %, irrespective of nozzle configuration. Yields improved when Eudragit® L 100-55 (EL) or Methocel® E6 (HPMC) was used in the inner fluid stream of the 3-fluid nozzle or in place of EE for the 2-fluid nozzle. Drug release from microparticles prepared with the 2-fluid nozzle was relatively rapid. Using EE in the outer fluid stream of the 3-fluid nozzle resulted in comparatively slower drug release, although drug release was observed, indicating that encapsulation was incomplete. Results from these studies also show that miscible polymers used in the two fluid streams mix during the spray drying process. In addition, findings from this study indicate that the polymer used in the inner fluid stream can impact drug release.

Open-Label Study of the Stability of Sublingual Nitroglycerin Tablets in Simulated Real-Life Conditions.

Contemporary practice favors refilling sublingual nitroglycerin (SL NTG) every 3 to 6 months. This recommendation is based on antiquated data that does not consider the reformulated tablet and the improved manufacturing process. Our objective was to investigate the stability of SL NTG over time using simulated real-life scenarios in comparison to controlled storage conditions. This was an open-label study of 100- and 25-count commercial SL NTG bottles stored in either controlled temperature and relative humidity conditions, or carried in a pocket or purse. SL NTG potency (chemical stability) was assessed using high performance liquid chromatography and physical stability was assessed by changes in tablet weights over time through the labeled expiration date. Both chemical and physical stability of SL NTG were affected by environmental and physical factors. High temperature storage resulted in the most rapid loss of potency. Tablets carried in a pant pocket lost potency faster than those carried in a purse. Potency was also dependent on headspace of the bottle. Tablets stored in the original bottle in a temperate environment could be expected to maintained potency for more than 2 years when carried in a purse, irrespective of package size. When carried in a pant pocket, potency of a 25-count bottle was maintained for 2 years, whereas potency of a 100-count bottle fell below acceptable limits at 12 months. In conclusion, since potency is dependent on temperature, headspace, and carrying practices, frequency of SL NTG refills should be based on individual patient behavior.

Use of polymers for taste-masking pediatric drug products.

Many drugs are bitter and overcoming this bitter taste is a major barrier in developing a successful product, especially for pediatric patients. Approaches to mask taste include changing taste perception, creating a physical barrier to separate the drug from interacting with taste buds, and changing drug solubility. This review is focused on polymers and the different ways these materials are used to achieve taste masking. Attention is given to systems that are easily swallowed, as swallowability is another concern in developing palatable products for pediatrics. Variables that should be considered when selecting a taste-masking approach are also presented.

Influence of relative humidity during coating on polymer deposition and film formation.

The influence of relative humidity in the pan during coating on polymer deposition and film formation was investigated. Four tablet substrates, differing in hydrophobicity, porosity, and surface roughness, were prepared and coated with Eudragit(®) RS/RL 30 D (8:2 ratio). The spray rate and atomization air pressure were varied to create two distinct micro-environmental conditions in the coating pan. PyroButton data logging devices placed directly in the pan were found to more accurately reflect the relative humidity to which tablets were exposed in comparison to measurements taken at the exhaust. Polymer deposition was shown to be influenced by the properties of the substrate, rather than the processing conditions used during coating, with higher polymer weight gains observed for the more porous tablets. Differences in the film-tablet interface and in the release performance of the coated products, however, were attributed to both the relative humidity in the pan and tablet porosity. Overall, this study demonstrated that a more humid coating process (86% vs 67%) promoted surface dissolution and physical mixing of the tablet ingredients with the forming film and the extent of this phenomenon was dependent on the tablet porosity.

Effect of Antiadherents on the Physical and Drug Release Properties of Acrylic Polymeric Films.

Antiadherents are used to decrease tackiness of a polymer coating during both processing and subsequent storage. Despite being a common excipient in coating formulae, antiadherents may affect mechanical properties of the coating film as well as drug release from film-coated tablets, but how could addition of antiadherents affect these properties and to what extent and is there a relation between the physical characteristics of the tablet coat and the drug release mechanisms? The aim of this study was to evaluate physical characteristics of films containing different amounts of the antiadherents talc, glyceryl monostearate, and PlasACRYL(TM) T20. Eudragit RL30D and Eudragit RS30D as sustained release polymers and Eudragit FS30D as a delayed release material were used. Polymer films were characterized by tensile testing, differential scanning calorimetry (DSC), microscopic examination, and water content as calculated from loss on drying. The effect of antiadherents on in vitro drug release for the model acetylsalicylic acid tablets coated with Eudragit FS30D was also determined. Increasing talc concentration was found to decrease the ability of the polymer films to resist mechanical stress. In contrast, glyceryl monostearate (GMS) and PlasACRYL produced more elastic films. Talc at concentrations higher than 25% caused negative effects, which make 25% concentration recommended to be used with acrylic polymers. All antiadherents delayed the drug release at all coating levels; hence, different tailoring of drug release may be achieved by adjusting antiadherent concentration with coating level.

Influence of temperature and relative humidity conditions on the pan coating of hydroxypropyl cellulose molded capsules.

In a previous study, hydroxypropyl cellulose (HPC)-based capsular shells prepared by injection molding and intended for pulsatile release were successfully coated with 10mg/cm(2) Eudragit® L film. The suitability of HPC capsules for the development of a colon delivery platform based on a time dependent approach was demonstrated. In the present work, data logging devices (PyroButton®) were used to monitor the microenvironmental conditions, i.e. temperature (T) and relative humidity (RH), during coating processes performed under different spray rates (1.2, 2.5 and 5.5g/min). As HPC-based capsules present special features, a preliminary study was conducted on commercially available gelatin capsules for comparison purposes. By means of PyroButton data-loggers it was possible to acquire information about the impact of the effective T and RH conditions experienced by HPC substrates during the process on the technological properties and release performance of the coated systems. The use of increasing spray rates seemed to promote a tendency of the HPC shells to slightly swell at the beginning of the spraying process; moreover, capsules coated under spray rates of 1.2 and 2.5g/min showed the desired release performance, i.e. ability to withstand the acidic media followed by the pulsatile release expected for uncoated capsules. Preliminary stability studies seemed to show that coating conditions might also influence the release performance of the system upon storage.

Experimental and computational studies of physicochemical properties influence NSAID-cyclodextrin complexation.

The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native ß-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (S o) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an AL profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and S o of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.

Influence of process parameters on tablet bed microenvironmental factors during pan coating.

Recent studies have shown the importance of monitoring microenvironmental conditions (temperature, relative humidity) experienced by the tablet bed during a pan coating process, thereby necessitating the need to understand how various process parameters influence these microenvironmental conditions. The process parameters studied in this work include exhaust air temperature, spray rate, inlet airflow rate, gun-to-bed distance, coating suspension percent solids, and atomization and pattern air pressure. Each of these process parameters was found to have an impact on the tablet bed relative humidity (RH), as measured using PyroButton data logging devices. A higher tablet bed RH was obtained with an increase in spray rate and atomization air pressure and with a decrease in exhaust air temperature, inlet airflow rate, gun-to-bed distance, suspension percent solids, and pattern air pressure. Based on this work, it can be concluded that the tablet bed thermodynamic conditions are a cumulative effect of the various process conditions. A strong correlation between the tablet bed RH and the frequency of tablet coating defect (logo bridging) was established, with increasing RH resulting in a higher percent of logo bridging events.

Physical aging in pharmaceutical polymers and the effect on solid oral dosage form stability.

The application of a polymeric film to a solid oral dosage form can be an effective technique to modify drug release. Most polymers used for such purposes are amorphous in nature and are subject to physical aging. This physical aging phenomenon has been shown to cause changes not only in the mechanical and drug release properties of polymeric films, but also the permeability of these films due to a densification and decrease in free volume of the polymer as the material relaxes to an equilibrated thermodynamic state. Temperature, humidity, and additional excipients in the coating formulations have been shown to influence the aging process. This review article discusses the process of physical aging in films prepared from aqueous dispersions, describes various analytical techniques that can be used to investigate the aging process, and highlights strategies to prevent such aging.

Mechanisms of polymeric film formation.

Polymeric films are applied to solid dosage forms for decorative, protective, and functional purposes. These films are generally applied by a spray atomization process, where the polymer is sprayed onto the solid substrate. The mechanism by which films are formed is dependent on whether the polymer is in the dissolved or dispersed state. For solutions, film formation occurs as the solvent evaporates, since the polymer chains are intimately mixed. Film formation from polymeric dispersions, however, requires the coalescence of individual polymer spheres and interpenetration of the polymer chains. Films prepared from polymeric dispersions exhibit a minimum film forming temperature and processing conditions must exceed this temperature in order to form the film. In addition, these systems generally require post-coating storage in temperature and humidity controlled environments to ensure complete polymer coalescence. Incomplete coalescence can lead to significant changes in drug release over time. This review article highlights the basic science principles involved in film formation from both polymeric solutions and dispersions and the variables that influence these film formation processes.

An update on pharmaceutical film coating for drug delivery.

INTRODUCTION: Pharmaceutical coating processes have generally been transformed from what was essentially an art form in the mid-twentieth century to a much more technology-driven process. AREAS COVERED: This review article provides a basic overview of current film coating processes, including a discussion on polymer selection, coating formulation additives and processing equipment. Substrate considerations for pharmaceutical coating processes are also presented. EXPERT OPINION: While polymeric coating operations are commonplace in the pharmaceutical industry, film coating processes are still not fully understood, which presents serious challenges with current regulatory requirements. Novel analytical technologies and various modeling techniques that are being used to better understand film coating processes are discussed. This review article also examines the challenges of implementing process analytical technologies in coating operations, active pharmaceutical ingredients in polymer film coatings, the use of high-solids coating systems and continuous coating and other novel coating application methods.

A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice.

Oral gavage dosing can induce stress and potentially confound experimental measurements, particularly when blood pressure and heart rate are endpoints of interest. Thus, we developed a pill formulation that mice would voluntarily consume and tested the hypothesis that pill dosing would be significantly less stressful than oral gavage. C57Bl/6 male mice were singly housed and on four consecutive days were exposed to an individual walking into the room (week 1, control), a pill being placed into the cage (week 2), and a dose of water via oral gavage (week 3). Blood pressure and heart rate were recorded by radiotelemetry continuously for 5h after treatment, and feces collected 6-10h after treatment for analysis of corticosterone metabolites. Both pill and gavage dosing significantly increased mean arterial pressure (MAP) during the first hour, compared to control. However, the increase in MAP was significantly greater after gavage and remained elevated up to 5h, while MAP returned to normal within 2h after a pill. Neither pill nor gavage dosing significantly increased heart rate during the first hour, compared to control; however, pill dosing significantly reduced heart rate while gavage significantly increased heart rate 2-5h post dosing. MAP and heart rate did not differ 24h after dosing. Lastly, only gavage dosing significantly increased fecal corticosterone metabolites, indicating a systemic stress response via activation of the hypothalamic-pituitary-adrenal axis. These data demonstrated that this pill dosing method of mice is significantly less stressful than oral gavage.

Novel low-molecular-weight hypromellose polymeric films for aqueous film coating applications.

The concentration of hypromellose (HPMC) is known to significantly impact the viscosity of coating solutions. The purpose of this study was to determine the viscosity of novel low-molecular-weight (LMW) HPMC products as a function of polymer concentration. The mechanical properties and water vapor permeability of free films prepared from these novel LMW HPMC polymers were also determined and the results were compared with films prepared with conventional HPMC. Solutions of LMW and conventional HPMC 2910 and 2906 containing up to 40% polyethylene glycol (PEG) 400 were prepared and the viscosities were measured using a Brookfield viscometer. Solutions were then cast onto glass plates and stored at 30?C and 50% relative humidity until films were formed. A Chatillon digital force gauge attached to a motorized test stand was used to quantify the mechanical properties of the films, whereas water vapor permeabilities were determined according to the ASTM E96 M-05 water method. As expected, the novel LMW polymer solutions exhibited significantly lower viscosities than the conventional comparators at equivalent polymer concentrations. Film strength of the LMW materials was lower than films prepared from the conventional HPMC solutions, although this effect was not as evident for the HPMC 2906 chemistry. Increasing concentrations of the plasticizer resulted in decreased tensile strength and Young?s modulus and increased elongation as well as increased water vapor permeability, irrespective of polymer type. No statistical difference was found between the tensile strength to Young?s modulus ratios of the F chemistry LMW and conventional HPMC polymer films.

Stable isotope-labeled excipients for drug product identification and counterfeit detection.

PURPOSE: Counterfeit drug products have become a major problem worldwide and a number of techniques to detect counterfeit products or reduce the potential for counterfeiting have been investigated. This study examined the use of stable isotope-labeled excipients in solid dosage forms as a method to identify drug products and to detect counterfeits. METHODS: (2)H- and (13)C-glucose were used as model excipients and incorporated in wet granulated formulations at a variety of different isotopic ratios. The ratios of (2)H/(1)H and (13)C/(12)C in each product were then determined by isotope ratio mass spectrometry. RESULTS: Results demonstrated the ability to detect the isotope-labeled glucose in both granules and tablets. CONCLUSIONS: It was possible to use the isotope ratios to differentiate between specific batches of granules, demonstrating the potential of this technique for in-product, batch-specific identification.

An activated renin-angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice.

It has been postulated that fetal vascular abnormalities in aryl hydrocarbon receptor null (ahr(-/-)) mice may alter cardiovascular homeostasis in adulthood. We tested the hypothesis that blood pressure regulation in adult heterozygous mice (ahr(+/-)) would be normal, compared to ahr(-/-) mice, since no vascular abnormalities have been reported in the heterozygote animals. Mean arterial blood pressure (MAP) was measured using radiotelemetry prior to and during treatment with inhibitors of the autonomic nervous system, nitric oxide synthase (NOS), angiotensin converting enzyme (ACE), or endothelin-1 A receptor (ET(A)). Also, indices of renin-angiotensin system (RAS) activation were measured. ahr(+/-) and ahr(-/-) mice were normotensive and hypotensive, respectively, compared to wild-type (ahr(+/+)) littermates. Responses of all genotypes to autonomic nervous system inhibition were normal. ahr(+/-) mice responded normally to NOS inhibition, while the responses of ahr(-/-) mice were significantly blunted. In contrast, ahr(+/-) mice were significantly more responsive to inhibition of ACE, an ET(A) antagonist, or both, while ahr(-/-) mice were significantly less responsive to ACE inhibition and more responsive to an ET(A) antagonist. ahr(+/-) mice also exhibited significant increases in plasma renin and ACE activity, plasma sodium, and urine osmolality, indicative of RAS activation. Thus, normotension in ahr(+/-) mice appears to be maintained by increased RAS and ET-1 signaling, while hypotension in ahr(-/-) mice may result from decreased RAS signaling. In conclusion, despite the lack of overt fetal vascular abnormalities in ahr(+/-) mice, the loss of a single ahr allele has a significant effect on blood pressure regulation.

Techniques to assess film coatings and evaluate film-coated products.

BACKGROUND: Polymeric film coatings have been applied to pharmaceutical solids for decorative, protective, or functional purposes. The application process is quite complex, with variables related to the coating formulation, substrate properties, processing parameters, and interactions thereof, all of which can affect product performance. OBJECTIVE: This article describes a number of experimental techniques used to determine the physical, mechanical, adhesive, thermal, and permeability properties of free and applied films. These analytical tools can be used to optimize product performance, advance our knowledge of the film formation process, and investigate interactions between the coating and the solid surface. CONCLUSION: Through a better understanding of film-coating processes, the cause of problems that arise during manufacturing, defects observed in the coating, and changes in performance upon subsequent storage may be more quickly and accurately resolved.

Clinical pharmacokinetics of oral controlled-release 5-fluorocytosine.

5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B to treat Cryptococcus neoformans meningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediate-release product demonstrated 80% release at 0.28 h, as determined in vitro by the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P < 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitro dissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.

Investigation into the mechanism by which cyclodextrins influence transdermal drug delivery.

The objective of this study was to investigate the mechanism by which hydroxypropyl-beta-cyclodextrin (HPCD) increases transdermal permeation. Hairless mouse skin was pretreated with HPCD solutions for up to 4 h. After removing the HPCD, corticosteroid-containing suspensions were applied and the transdermal flux and skin accumulation of two model drugs were investigated. After pretreatment, changes to the stratum corneum endothermic melting transitions were determined as an indication of HPCD-induced lipid disorganization. Results demonstrated that HPCD pretreatment had no significant effect on the transdermal permeation or skin accumulation of the model corticosteroids. These findings suggest that HPCD functions to enhance the apparent solubility of the drug in the formulation, thus increasing transdermal permeation rather than extracting lipids from the skin.