Release of Hydrocortisone from Creams - Experiments and Simulations Henrik Svederud Department of Chemical Engineering, Lund University, Abstract The aim of this Master thesis was to formulate models for the release of hydrocortisone (HC) and one of its derivatives, hydrocortisone succinate (HC-Succ), from a commercially available cream. The models described the transport in the cream and the release from the cream. The models were verified with real dissolution analysis. The cream was an o/w emulsion stabilized using a non-ionic surface-active lipid. The release showed to be dependent on the solubility of the substance and on the concentration but independent on the size of the oil droplets. Three models were formulated: the water-dissolved model, the oil-dissolved model and the crystal model. The models were based on assumptions regarding where and in what form the active pharmaceutical ingredient (API) was assumed to exist in the cream. The water-dissolved model was concluded to describe the release of HC-Succ and the crystal model was concluded to describe the release of HC. Introduction The skin provides a painless and patient-friendly interface for drug administration. Apart from diminished side effects and avoiding first pass metabolism, the transdermal route provides sustained and controlled delivery. Hydrocortisone creams are prime examples of topical formulations [, ]. Materials The formulation of the cream is shown in table [3]. Table. The cream formulation [3]. Substance w/w (%) CPL-Evening Primrose Oil (EPO) Cetostearyl alcohol (Lanette) 7 Glyceryl stearate (Admul MG) Glycerin Surface active lipid (emulsifier) - API.- Water, de-ionized Ad HC, see figure, is a glucocorticoid widely used in dermal formulations for treating allergies and inflammations. Carbon Figure. The structural formula of hydrocortisone. The substitutent for HC-Succ is linked to carbon. Data for the two substances are shown in table. Hydrocortisone acetate was also used when the release for substances with different solubility in water was compared. Table 3. API used in the experiments, molecular weight and solubility data are included [3]. Substance MW (g/mol) HC 36.8 HC-Ac 4. HC-Succ 48 Solubility (mg/ml) Experimental Manufacturing of creams When making the creams the oil phase always constituted of EPO, cetostearyl alcohol and glyceryl stearate. The water phase always constituted of water, glycerine and the surfaceactive lipid. HC-Succ was added to the water phase. HC and HC-Ac were added to the oil phase. Each phase was stirred by a magnetic stirrer and heated to 6 o C separately. Then the oil phase was added to the water phase during either homogenization by a disperser or stirring by magnetic stirrer [3]. Size measurement The creams were viewed in light microscope CETI triton and photographed by video camera Hitachi KP-D4. The software, Image-Pro Plus., was used for droplet size measurements. The diameter of the droplets was measured; the droplets were counted and grouped into size-
groups. The mean surface diameter (d s ) was calculated by [3]: d s = nd n m () n are numbers in each size group and d m is the mean of each size group. Dissolution analysis The release of API from the creams was evaluated in-vitro via dissolution bath Prolabo in phosphate-citrate buffer (ph.) with % EtOH, modified from Ph.Eur. 4 th ed, (ref.487). Approximately g of cream were put in each dissolution cell. The surface was covered with a dialysis. The was a regenerated cellulose dialysis (Spectra/Por 4, MWCO - 4, Spectrum laboratories Inc.). The area of the was 4.9cm and the cream layer was mm thick. The dissolution tests were run for 4h at 37 o C and rpm. The release was analysed in silica cuvettes by UV-Vis spectrophotometer HP843 (Hewlett-Packard). The absorbance was read at 48nm. The phosphate-citrate buffer with % EtOH was used as blank in the measurements [3]. Diffusion cell To determine the diffusivity a so-called diaphragm-cell was used. The lower compartment was filled with (V low ) of.3mg/ml HC-solution (C low, ). The upper compartment was filled with (V up ) water (C up, =). Between the two volumes were two dialysis s with some medium (cream or water) between. The medium formed a.73mm (δ) thick layer between the two s. The area was.34cm. The two volumes were well stirred at rpm. In order to calculate the diffusion resistance in the s the volume between the s was filled with water instead of cream. The concentration in the upper compartment was measured using a spectrophotometer (Shimadzu UV-6, Shimadzu Corporation) at 48nm. Water was used as the blank. The effective D e was calculated using eq. [4, ]. D e At δ V low V up C = ln C low low, C C up up, () The total diffusion resistance consists not only of the resistance through the cream but also of the resistance in the s. The total mass transfer resistance is thus the sum of mass transfer resistances according to eq. 3 [6]. δ δ δ = (3) tot cream D e, tot De, cream De, Models General assumptions A number of assumptions were made for the modelling of the release from the creams. Following general assumptions were made: The oil particles were spherical in shape and monodisperse. The oil droplets were perfectly distributed in the cream and had no velocity in the continuous phase. The receiving chamber was a perfect sink. o mass transfer resistance in the. Assumptions for the water-dissolved model The model for the highly water soluble HC-Succ was called the water-dissolved model. Following assumption was made for the water-dissolved model: All API was initially dissolved in the water phase. Assumptions for the oil-dissolved model This model was formulated for HC. Following assumptions for this model were made: Saturation concentration in the water phase. The rest dissolved in the oil phase. Saturation concentration on the surface of the oil droplets. Assumptions for the crystal model This model was formulated for HC as an alternative to the oil-dissolved model. Following assumptions for this model were made: Saturation concentration in the water phase. The rest suspended in the continuous phase as crystals. Monodisperse crystals (4µm [3]) and spherical in shape. Mass transfer The model used to describe the diffusion of API in the cream was an unsteady-state distributed model. The type of PDE:s used was the parabolic (diffusion type). [7]. Eq. 4 describes
how the concentration (C) of API in the continuous phase changed with time (t). C C kas ( Cs C) = De t V (4) D e is the effective diffusion coefficient, x the distance, A s the total particle surface area, C s the saturation concentration and V the volume. The first term describes the diffusion of API in the continuous phase and the second term describes the diffusion from particles suspended in the cream. In the water-dissolved model the second term in eq. 4 didn t exist. The PDE:s was solved numerically using the method of lines (MOL). The second order term was descretized in space by centered-difference approximation according to eq. [7]. h=x i -x i- = x i -x i C C i Ci h C i () Following boundary conditions (BC) were set: At x=, C = At x=l, C De = k ( Csin k C) The PDE:s were solved using ODEs in Matlab 6. (MathWorks Inc.). Effective diffusion coefficient For the water-dissolved and the oil-dissolved model the effective diffusion coefficient (D e ) was estimated using eq. 6 [4]. ε D e = D τ (6) D is the diffusion coefficient in water, ε the void fraction and τ the tortuosity. Following values were set in order to calculate an initial diffusion coefficient (D e ): D = 4. -4 cm /min (Sucrose in water, dilute solution, MW: 34, 37 o C)[4] ε=.8 (Volume fraction of water in the cream) τ=.3 (Estimation) Using eq. 6: D e =.6-4 cm /min D e was adjusted to fit the simulations to the experimental results in the water-dissolved and the oil-dissolved models. For the crystal model D e for HC in the cream was determined experimentally using the diffusion cell and eq. and 3. The result was D e =.6-4 cm /min. Mass transfer coefficients For the mass transfer coefficient at the boundary between the cream and the receiving bulk the correlation described by eq. 7 was used []. k d D 6 / / 3 = Sh =. Re Sc (7) k is the mass transfer coefficient at the, D diffusivity in water, d the diameter of the, Sh the Sherwood number, Re Reynolds number and Sc the Schmidt number. The result from the calculations was: k =.cm/min For the oil-dissolved model, the mass transfer coefficient at the phase boundary between the oil and the water phase was described by eq. 8 []. D Sh e k pb = (8) ds k pb is the mass transfer coefficient for the boundary layer between the oil and water phases. The oil droplets were assumed to have no velocity in the continuous phase, hence Sh =. For the crystal model the mass transfer coefficient k L was a lumped coefficient including both the mass transfer and the dissolution kinetics. It was used as the fitting parameter. Results and discussion Dissolution analysis Figure shows the release results for HC, HC- Succ and HC-Ac. API-concentration was % and oil droplet size 9µm. Percentage dissolved API (%) 6 4 Average release profiles for different API:s (C=%) HC-Succ HC HC-Ac Figure. Average release profiles for different API:s. 3
The release was dependent on the solubility of the API. Higher solubility gave faster release. The relation between the HC-concentration and the release is shown in figure 3. The oil droplet size was kept constant. Mean release profiles for different HC-concentrations (ds constant) 7 6 C=.% Percentage dissolved HC-Succ (%) 7 6 4 Simulation of the release of HC-Succ (C=%) De/ De/ 4 C=.% C=% C=.% C=% Figure. Results from the simulation of the release of HC- Succ as the API. Figure 3. Mean relative release for creams with different initial HC-concentration. Oil droplet size was 9µm. Table 3. Diffusion and mass transfer coefficients for cream containing % HC-Succ. API D e,up D e,low (cm / (cm / HC-Succ. -. -6 The relative release was higher with lower concentration of HC. The release curve for.% lies above the one for %. This was considered to lie within the marginal of error. The relation between the oil droplet size and release was investigated. HC-concentration was kept constant (%). Results from the dissolution analysis are shown in figure 4. Mean release profiles for crems with different droplet sizes (ds in micrometers, C=%) 4 4 It was possible to fit the simulations to the experimental results quite well except for the very start of the release where the simulations showed a faster release. The high concentration of HC-Succ in the water phase lowered the value of D e. Simulations using the oil-dissolved model The simulation results for the release of HC are shown in figure 6 and table 4. 4 Simulation of the release of HC (C=%) 3 ds=3 ds=4 ds=7 ds= ds=9 4 3 De/. De/7 Figure 4. Average release profiles for different mean surface diameters of the oil droplets. The HC-concentration in the creams was %. There was no relation between the mean surface diameter of the oil droplets and the dissolution rate. The result can be seen as an evidence for that the oil-dissolved model wasn t valid for this system. Figure 6. Results from the simulation of the release of HC with initial concentration % and droplet size 9µm. For HC good compliance between the simulations and the experimental results was achieved. As for HC-Succ the simulated release was much faster than the experimental in the start. Simulations using the water-dissolved model Figure and table 3 show the results for the simulations of the release of HC-Succ. 4
Table 4. Actual effective diffusion and mass transfer coefficients for creams with different concentrations of HC. Conc. (%) D e,up (cm / k pb,up (cm/ D e,low (cm / k pb,low (cm/.. -.. -.34..3-4.9.9 -.64. -4.3 3.7 -.8..3-4.9 6. -.4. -4.3.8 -.3 The D e, up and k pb, up was about the same size for all the concentrations. There were some differences between for the lower values. Simulations using the crystal model The results for the simulations of the release of HC are shown in figure 7. 4 4 3 Simulation of the release of HC (C=%) kl=*-4cm/min kl=*-cm/min Figure 7. Results from the simulation of the release of HC with the initial concentration %. It was possible to get good fitting between the simulated and the experimental release curves. Table show the result for the simulation of various HC-concentrations. Table. Resulting lumped mass transfer coefficients for different concentrations of HC. Concentration of HC (%) Upper k L (cm/. - -. -3 3 - -4 -. -3-4 8-4 - Lower k L (cm/ Fitting between the simulations and the experiments could be done. Overall the fitting with the upper bound was better than the fitting with the lower bound. The lower value of k L compared to k pb in the oil-dissolved model. Conclusions The release of HC-Succ was concluded to be described be the water-dissolved model. It would be interesting to determine the D e experimentally. It probably varies, as the concentration in the continuous phase gets lower. The crystal model better described the release of HC than the oil-dissolved model. The reason for this is that the release was independent on the oil-droplet size. According to the oil-dissolved model the release should be faster with smaller oil droplets due to bigger surface area. According to Wahlström [3] and Ek [8] the solubility of HC in EPO is as low as.%. References [] Samir Mitragotri, Breaking the skin barrier, Advanced Drug Delivery Reviews 6, 4, -6. [] Edith Mathiowitz, Encyclopedia of Controlled Drug Delivery, vol, John Wiley & Sons Inc, 999, 976-99. [3] Sophia Wahlström, Investigation of Formulation Factors on Physical Stability and Dissolution Behaviours of Hydrocortisone and Hydrocortisone Derivatives From an O/W Cream, Master thesis, Lund University, Sweden, 4. [4] Christie J. Geankoplis, Transport Processes and Unit Operations, 3 rd ed, Prentice-Hall International, 993. [] E.L Cussler, Diffusion: Mass Transfer in Fluid Systems, Cambridge University Press, nd ed, 3, 6-8. [6] Susanne Fredenberg, PLG Films in Controlled Release Pharmaceuticals Diffusion and Degradation, Licentiate thesis, Department of Chemical Engineering, Lund University, Sweden, 4. [7] Bernt ilsson, Process Simulation Using MATLAB, Department of Chemical Engineering, Lund University,, 8-67. [8] Cecila Ek, Investigation of Formulation Factors Influencing the Physical Stability, Viscosity and Dissolution Behaviours From an o/w Lotion With Hydrocortisone As Model Substance, Master thesis, Division of Food Technology, Lund University,. Acknowledgements This work was carried out as a Master Degree work at Department of Chemical Engineering, Lund University and at Galenica AB, Malmö. With Professor Andes Axelsson, Henri Hansson and ils-olof Lindberg as Supervisors.