Non-destructive monitoring of creaming of oil-in-water emulsion-based formulations using magnetic resonance imaging

Machida

Yokawa³

et al. 2015

Self Cite

A cream that contains menthol and diphenhydramine is widely prepared in hospital pharmacies and prescribed to patients for the treatment of pruritus associated with chronic kidney disease. However, there is a serious concern regarding its physical stability; therefore, we investigated this issue using magnetic resonance imaging (MRI). For a sample preparation, a menthol-containing ethanol solution was mixed with a commercial diphenhydramine cream. After storage for 7 d at 40°C, substantial phase separation into two distinct layers (upper and lower layers) was observed in the sample. This study further examined the components of the phase-separated layers using magnetic resonance (MR) spectroscopy and chemical shift selective images, and it was verified that the upper layer consisted of packed oil droplet layers, whereas the lower was an aqueous phase. Subsequently, the time-dependent phase separation of the sample at different temperatures was investigated. From the MR images, including a T 2 relaxation time map and apparent diffusion coefficient maps, it was obvious that the phase separation developed further with increasing temperature; the most substantial phase separation was observed from the sample stored at 40°C, while no phase separation was detected at 25°C. In the final phase of this study, we conducted a formulation study and succeeded in improving the cream's physical stability by adding a hydrophilic surfactant to the preparation.

Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Magnetic Resonance Imaging Study on the Physical Stability of Menthol and Diphenhydramine Cream for the Treatment of Chronic Kidney Disease-Associated Pruritus

Machida

Yokawa³

et al. 2015

Self Cite

“…[10][11][12][13] MRI is a popular molecular imaging method using the principle of NMR. 14) As well as nondestructive monitoring of a sample, it enables visualization of the molecular mobility of a sample using magnetic resonance (MR) parameters.…”

Section: )mentioning

confidence: 99%

“…It is worth noting that the detection sensitivity of change in the emulsion state is much superior to that by visible observation. 12,15) The creams containing various surfactants were stored at 40°C, and their phase separations were monitored continuously. As shown in Fig.…”

Section: Effects Of Surfactants On the Emulsion Stability Of The Creammentioning

confidence: 99%

Effect of Surfactants and Thickeners on the Stability of Menthol–Diphenhydramine Cream Identified by Magnetic Resonance Imaging

Yokokawa

Utsumi

et al. 2016

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A menthol-diphenhydramine cream is prepared in hospital pharmacies and then prescribed to patients for the treatment of pruritus associated with chronic kidney disease. The purpose of this study is to design a stable formulation without any concern about phase separation during its clinical use on patients. As a preventive measure against phase separation, various surfactants and thickeners were incorporated into the creams. The test creams were stored at 40°C, and then their phase separation behaviors were monitored. The key technology was magnetic resonance imaging T 2 mapping. From the T 2 maps, some surfactants showed a certain stabilizing effect. In addition, the data analysis using Kohonen's self-organizing map revealed that hydrophilic-lipophilic balance of the surfactant is an important factor for the stabilizing effects of the surfactants. However, as a whole, the effect of surfactant was not sufficient to improve completely the low stability. By contrast, the creams were significantly stabilized by addition of thickeners. In particular, the stabilizing effect of carbomer Hiviswako105 ® (H105) was very high; no phase separation was observed from the cream containing H105 even after 30 d storage at 40°C. This study also verified the combination effect of surfactants and thickeners on the improvement of the emulsion stability. In conclusion, we successfully established a stable formulation of menthol-diphenhydramine cream.

“…[2][3][4] MRI is one of the most popular molecular imaging methods; it permits the nondestructive monitoring of a sample using the principle of nuclear magnetic resonance (NMR). In addition, MRI can visualize the state of water in a sample by using magnetic resonance (MR) parameters.…”

mentioning

confidence: 99%

Self-organizing Map Analysis for Understanding Comprehensive Relationships between Formulation Variables, State of Water, and the Physical Stability of Pharmaceutical Emulsions

Hasegawa

Horita³

et al. 2015

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The physical stability of pharmaceutical emulsions is an important quality attribute to be considered. To obtain a better understanding of this issue, this study investigated the contribution of the state of water to the physical stability of pharmaceutical emulsions. The key technology to evaluate the state of water was magnetic resonance imaging (MRI). For sample preparation, model emulsions with different formulation variables (surfactant content, water content, and hydrophilic-lipophilic balance) were prepared. The T 1 relaxation time, diffusion coefficient, and viscosity were measured as physical properties. The physical stability of the samples was evaluated using apparent diffusion coefficient maps acquired by MRI. Data analysis of the observed data was performed using the nonlinear response surface method and Kohonen's self-organizing map (SOM). It was determined that, depending on the formulation variables, the state of water was substantially changed and it played a significant role in the physical stability. SOM analysis successfully classified the conditions of formulation variables into four distinct clusters in terms of the similarity of the physical properties of the resultant emulsions, and then clarified the characteristics of the stable emulsions. This study provided us with a comprehensive understanding of the formulation variables, physical properties, and stability concerning the preparation of the model emulsion.Key words pharmaceutical emulsion; magnetic resonance imaging; physical stability; T 1 relaxation time; diffusion coefficient Oil-in-water type emulsions are widely used for various semisolid topical dosage forms. Pharmaceutical emulsions are less greasy than ointments, they are easier to apply and can be easily washed off from the skin surface; thus, they are highly acceptable to patients. 1) For the development of pharmaceutical emulsions, physical stability is a very important quality attribute to be considered. This is because emulsions are thermodynamically unstable by nature. In general, the destabilization processes of emulsions are classified into four distinct processes: creaming, flocculation, coalescence, and Ostwald ripening.1) Coalescence and Ostwald ripening are the most serious types of destabilization, whereas creaming and flocculation are subtle destabilization processes.We have been investigating the physical stability of pharmaceutical emulsions using magnetic resonance imaging (MRI).2-4) MRI is one of the most popular molecular imaging methods; it permits the nondestructive monitoring of a sample using the principle of nuclear magnetic resonance (NMR). In addition, MRI can visualize the state of water in a sample by using magnetic resonance (MR) parameters. In a previous study, we established a new method to monitor destabilization processes of pharmaceutical emulsions.4) The key technology is the visualization of the state of water. Water in pharmaceutical emulsions can exist in various states depending on its particular location and microenvironment.2) Once cre...