A pharmaceutical dosage form is an entity that is administered to patients so that they receive an effective dose of an active pharmaceutical ingredient (API). The proper design and formulation of a transdermal dosage form require a thorough understanding of the physiological factors affecting percutaneous penetration and physicochemical characteristics of the API, as well as that of the pharmaceutical exipients that are used during formulation. The API and pharmaceutical excipients must be compatible with one another to produce a formulation that is stable, efficacious, attractive, easy to administer, and safe (Mahato, 2007:11). Amongst others, the physicochemical properties indicate the suitability of the type of dosage form, as well as any potential problems associated with instability, poor permeation and the target site to be reached (Wells & Aulton, 2002:337). Therefore, when developing new or improved dosage forms, it is of utmost importance to evaluate the factors influencing design and formulation to provide the best possible dosage form and formulation for the API in question. Delivery of an API through the skin has long been a promising concept due to its large surface area, ease of access, vast exposure to the circulatory and lymphatic networks, and non-invasive nature of the therapy. This is true whether a local or systemic pharmacological effect is desired (Aukunuru et al., 2007:856). However, most APIs are administered orally as this route is considered to be the simplest, most convenient and safest route of API administration. Since ibuprofen is highly metabolised in the liver and gastrointestinal tract, oral administration thereof results in decreased bioavailability. Furthermore, it also causes gastric mucosal damage, bleeding and ulceration. Another obstacle associated with oral API delivery is that some APIs require continuous delivery which is difficult to achieve (Bouwstra et al., 2003:3). Therefore, there is significant interest to develop topical dosage forms for ibuprofen to avoid side effects associated with oral delivery and to provide relatively consistent API levels at the application site for prolonged periods (Rhee et al., 2003:14). The aim of this study was to determine the influence of selected formulation factors on the transdermal delivery of ibuprofen. In order to achieve this aim, the physicochemical properties of ibuprofen had to be evaluated. The aqueous solubility, pH-solubility profile, octanol-water partition coefficient (log P-value) and octanol-buffer distribution coefficient (log D-values, pH 5 and 7.4) of ibuprofen were determined. According to Naik et al., (2000:319) the ideal aqueous solubility of APIs for transdermal delivery should be more than 1 mg.ml-1. However, results showed that ibuprofen depicted an aqueous solubility of 0.096 mg.ml-1 ± 25.483, which indicated poor water solubility and would therefore be rendered less favourable for transdermal delivery if only considering the aqueous solubility. The pH-solubility profile depicted that ibuprofen was less soluble at low pH-values and more soluble at higher pH-values. Previous research indicated that the ideal log Pvalues for transdermal API permeation of non steroid anti-inflammatory drugs (NSAIDs) are between 2 and 3 (Swart et al., 2005:72). Results obtained during this study indicated a log P-value of 4.238 for ibuprofen. This value was not included in the ideal range, which is an indication that the lipophilic/hydrophilic properties are not ideal, and this might therefore; contribute to poor ibuprofen penetration through the skin. Furthermore, the obtained log D-values at pH 5 and 7.4 were 3.105 and 0.386, respectively. Therefore, it would be expected that ibuprofen incorporated into a formulation prepared at a pH of 5 would more readily permeate the skin compared to ibuprofen incorporated into a formulation prepared at a pH of 7.4. A gel, an emulgel and a Pheroid™ emulgel were formulated at pH 5 and 7.4, in order to examine which dosage form formulated at which pH would deliver enhanced transdermal delivery. Obtained diffusion results of the different semi-solid formulations were furthermore compared to a South African marketed commercial product (Nurofen® gel) in order to establish if a comparable formulation could be obtained. An artificial membrane was used to conduct the membrane permeation studies over a period of 6 h, in order to determine whether ibuprofen was in fact released from the formulations through the membrane. Skin permeation studies were conducted using Franz diffusion cells over a period of 12 h where samples were withdrawn at specified time intervals. All the formulations exhibited an increase in the average cumulative amount of ibuprofen released from the formulations and that permeated the membrane when compared to Nurofen® gel. This increase was statistically significant (p<0.05) for the gel, emulgel and Pheroid™ emulgel at pH 7.4. The gel at pH 7.4 exhibited the highest cumulative amount of ibuprofen that permeated the membrane. Preparations formulated at a pH of 5, did not differ significantly from Nurofen® when the average cumulative amount of ibuprofen that permeated the membrane were compared. The following rank order for the average cumulative amount released from the formulations could be established: Gel (pH 7.4) >>>> Pheroid™ emulgel (pH 7.4) > Emulgel (pH 7.4) >>> Gel (pH 5)> Pheroid™ emulgel (pH 5) ≈ Emulgel (pH 5) > Nurofen® gel. On the other hand, all the formulations exhibited an increase in the average cumulative amount of ibuprofen that permeated the skin when compared to Nurofen® gel. This increase was statistically significant (p < 0.05) for the gel, emulgel and Pheroid™ emulgel at pH 5, as well as the emulgel and Pheroid™ emulgel at pH 7.4. The emulgel at pH 5 exhibited the highest cumulative amount of ibuprofen that permeated the skin. The following rank order for the average cumulative amount released from the formulations and that permeated the skin could be established: Emulgel (pH 5) >> Pheroid™ emulgel (pH 5) > Gel (pH 5) > Emulgel (pH 7.4)> Pheroid™ emulgel (pH 7.4) ≈ Emulgel (pH 7.4) >> Nurofen® gel > Gel (pH 7.4). From this rank order it was clear that a trend was followed where the pH of formulation also played a role in ibuprofen permeation. All the formulations exhibited a higher release rate and flux when compared to Nurofen® gel. This was statistically significant for the emulgel, gel and Pheroid™ emulgel at pH 7.4. The gel at pH 7.4 exhibited the highest release rate and flux. This was observed for the membrane and skin permeation studies. All the formulations (including Nurofen® gel) presented a correlation coefficient (r2) of 0.972 – 0.995 for membrane permeation studies, and 0.950 – 0.978 for skin permeation studies; indicating that the release of ibuprofen from each of the formulations could be described by the Higuchi model. Furthermore, all the formulations exhibited a prolonged lag time compared to Nurofen® gel which indicated that the ibuprofen was retained for a longer time by the base. This was statistically significant (p < 0.05) for the emulgel at pH 7.4, the gel and Pheroid™ emulgel at pH 5. The gel at pH 7.4 exhibited a lag time closest to that of Nurofen® gel and this difference could not be classified as statistically significant (p > 0.286). This was observed for the membrane and skin permeation studies. Nurofen® gel exhibited the highest ibuprofen concentration in the stratum corneum as well as in the epidermis followed by the gel at pH 7.4. However, results obtained for all the formulations indicated that topical as well as transdermal delivery of ibuprofen was achieved. The pH of a formulation plays an important role with respect to API permeation. Ibuprofen is reported to have a pKa value 4.4 (Dollery, 1999:I1); and by application of the Henderson-Hasselbach equation, at pH 5, 20.08% of ibuprofen will be present in its unionised form and at pH 7.4, 0.1% ibuprofen will exist in its unionised form. Since the unionised form of APIs is more lipid soluble than the ionised form, unionised forms of APIs permeate more readily across the lipid membranes (Surber & Smith, 2000:27). Therefore, it would be expected that ibuprofen formulated at pH 5 would be more permeable than formulations at pH 7.4. However, this did not correspond to the results (membrane studies) obtained in this study. It may be attributed to the solubility of ibuprofen in the different formulations. According to the pH-solubility profile of ibuprofen obtained in this study, it was more soluble at pH 7.4 than at pH 5. This was due to the fact that ibuprofen is a weak acidic compound, and for every 3 units away from the pKa-value, the solubility changes 10-fold (Mahato, 2007:14). However, with regard to the skin permeation studies, enhanced permeation was obtained with the formulations prepared at pH 5. This was in accordance with Corrigan et al., (2003:148) who stated that NSAIDs are less soluble and more permeable at low pH values, and more soluble and less permeable at high pH values. This was most probably due to the fact that unionised species, although possessing a lower aqueous solubility than the ionised species, resulted in enhanced skin permeation due to being more lipid-soluble. Finally, stability tests on the different semi-solid formulations for a period of three months at different temperature and humidity conditions were conducted to determine product stability. The formulations were stored at 25 °C/60% RH (relative humidity), 30 °C/60% RH and 40 °C/75% RH. Stability tests included: mass variation, pH, zeta potential, droplet size, visual appearance, assay, and viscosity. No significant change was observed for mass variation, pH, zeta potential and droplet size over the three months for any of the different formulations stored at the different storage conditions. In addition, no significant change in colour was observed for the gel and emulgel formulations at pH 5 and 7.4 over the three months at all the storage conditions. However, it was observed that the formulations containing Pheroid™ showed a drastic change in colour at all the storage conditions. This might have been due to oxidation of certain components present in the Pheroid™ system. Consequently, further investigation is necessary to find the cause of the discolouration and a method to prevent it. The gel formulated at pH 5 depicted the formation of crystals. This might have been due to the fact that the solubility of ibuprofen was exceeded, leading to it precipitating from the formulation. A possible contributing factor to the varying assay values obtained during the study might have been due to non-homogenous sample withdrawal. On the other hand, no significant change was observed for the emulgel and Pheroid™ emulgel formulated at pH 5 and 7.4. The emulgel and Pheroid™ emulgel formulated at pH 5 depicted relative instability (according to the International Conference on Harmonisation of Technical Requirements For Registration of Pharmaceuticals for Human Use, ICH) only at 40 °C/75% RH with a change in ibuprofen content of more than 5% (6.78 and 6.46%, respectively). The gel, emulgel and Pheroid™ emulgel at pH 7.4 exhibited the least variation in ibuprofen concentration at all of the storage conditions. This might indicate that the pH at which a semi-solid formulation is produced will have a direct influence on the stability of the product. No significant changes in viscosity (%RSD < 5) was observed for the gel and emulgel formulated at pH 7.4 and stored at 25 °C/60% RH. The remaining formulations at all of the specified storage conditions exhibited a significant change in viscosity (%RSD > 5) with a decrease in viscosity being more pronounced at the higher temperature and humidity storage conditions. A possible contributing factor to the change in viscosity over three months at the specified storage conditions might have been due to the use of Pluronic® F-127 (viscosity enhancer). This viscosity enhancer possesses a melting point of approximately 56 °C (BAST Corporation. s.a). The problem with this might have been the temperature (70 °C) at which the formulations were prepared. The higher preparation temperature might have caused the Pluronic® F-127 to degrade, thereby losing its ability to function appropriately. A balance must be maintained between optimum solubility and maximum stability (Pefile & Smith, 1997:148). Despite the lower skin permeation of the gel formulated at pH 7.4, this formulation performed the best, as it was considered stable (least variation during the 3 month stability test) and the obtained tape stripping results showed that this formulation depicted the highest ibuprofen concentrations in the stratum corneum and epidermis. Thus, topical as well as transdermal delivery were obtained. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

A pharmaceutical dosage form is an entity that is administered to patients so that they receive an effective dose of an active pharmaceutical ingredient (API). The proper design and formulation of a transdermal dosage form require a thorough understanding of the physiological factors affecting percutaneous penetration and physicochemical characteristics of the API, as well as that of the pharmaceutical exipients that are used during formulation. The API and pharmaceutical excipients must be compatible with one another to produce a formulation that is stable, efficacious, attractive, easy to administer, and safe (Mahato, 2007:11). Amongst others, the physicochemical properties indicate the suitability of the type of dosage form, as well as any potential problems associated with instability, poor permeation and the target site to be reached (Wells & Aulton, 2002:337). Therefore, when developing new or improved dosage forms, it is of utmost importance to evaluate the factors influencing design and formulation to provide the best possible dosage form and formulation for the API in question. Delivery of an API through the skin has long been a promising concept due to its large surface area, ease of access, vast exposure to the circulatory and lymphatic networks, and non-invasive nature of the therapy. This is true whether a local or systemic pharmacological effect is desired (Aukunuru et al., 2007:856). However, most APIs are administered orally as this route is considered to be the simplest, most convenient and safest route of API administration. Since ibuprofen is highly metabolised in the liver and gastrointestinal tract, oral administration thereof results in decreased bioavailability. Furthermore, it also causes gastric mucosal damage, bleeding and ulceration. Another obstacle associated with oral API delivery is that some APIs require continuous delivery which is difficult to achieve (Bouwstra et al., 2003:3). Therefore, there is significant interest to develop topical dosage forms for ibuprofen to avoid side effects associated with oral delivery and to provide relatively consistent API levels at the application site for prolonged periods (Rhee et al., 2003:14). The aim of this study was to determine the influence of selected formulation factors on the transdermal delivery of ibuprofen. In order to achieve this aim, the physicochemical properties of ibuprofen had to be evaluated. The aqueous solubility, pH-solubility profile, octanol-water partition coefficient (log P-value) and octanol-buffer distribution coefficient (log D-values, pH 5 and 7.4) of ibuprofen were determined. According to Naik et al., (2000:319) the ideal aqueous solubility of APIs for transdermal delivery should be more than 1 mg.ml-1. However, results showed that ibuprofen depicted an aqueous solubility of 0.096 mg.ml-1 ± 25.483, which indicated poor water solubility and would therefore be rendered less favourable for transdermal delivery if only considering the aqueous solubility. The pH-solubility profile depicted that ibuprofen was less soluble at low pH-values and more soluble at higher pH-values. Previous research indicated that the ideal log Pvalues for transdermal API permeation of non steroid anti-inflammatory drugs (NSAIDs) are between 2 and 3 (Swart et al., 2005:72). Results obtained during this study indicated a log P-value of 4.238 for ibuprofen. This value was not included in the ideal range, which is an indication that the lipophilic/hydrophilic properties are not ideal, and this might therefore; contribute to poor ibuprofen penetration through the skin. Furthermore, the obtained log D-values at pH 5 and 7.4 were 3.105 and 0.386, respectively. Therefore, it would be expected that ibuprofen incorporated into a formulation prepared at a pH of 5 would more readily permeate the skin compared to ibuprofen incorporated into a formulation prepared at a pH of 7.4. A gel, an emulgel and a Pheroid™ emulgel were formulated at pH 5 and 7.4, in order to examine which dosage form formulated at which pH would deliver enhanced transdermal delivery. Obtained diffusion results of the different semi-solid formulations were furthermore compared to a South African marketed commercial product (Nurofen® gel) in order to establish if a comparable formulation could be obtained. An artificial membrane was used to conduct the membrane permeation studies over a period of 6 h, in order to determine whether ibuprofen was in fact released from the formulations through the membrane. Skin permeation studies were conducted using Franz diffusion cells over a period of 12 h where samples were withdrawn at specified time intervals. All the formulations exhibited an increase in the average cumulative amount of ibuprofen released from the formulations and that permeated the membrane when compared to Nurofen® gel. This increase was statistically significant (p<0.05) for the gel, emulgel and Pheroid™ emulgel at pH 7.4. The gel at pH 7.4 exhibited the highest cumulative amount of ibuprofen that permeated the membrane. Preparations formulated at a pH of 5, did not differ significantly from Nurofen® when the average cumulative amount of ibuprofen that permeated the membrane were compared. The following rank order for the average cumulative amount released from the formulations could be established: Gel (pH 7.4) >>>> Pheroid™ emulgel (pH 7.4) > Emulgel (pH 7.4) >>> Gel (pH 5)> Pheroid™ emulgel (pH 5) ≈ Emulgel (pH 5) > Nurofen® gel. On the other hand, all the formulations exhibited an increase in the average cumulative amount of ibuprofen that permeated the skin when compared to Nurofen® gel. This increase was statistically significant (p < 0.05) for the gel, emulgel and Pheroid™ emulgel at pH 5, as well as the emulgel and Pheroid™ emulgel at pH 7.4. The emulgel at pH 5 exhibited the highest cumulative amount of ibuprofen that permeated the skin. The following rank order for the average cumulative amount released from the formulations and that permeated the skin could be established: Emulgel (pH 5) >> Pheroid™ emulgel (pH 5) > Gel (pH 5) > Emulgel (pH 7.4)> Pheroid™ emulgel (pH 7.4) ≈ Emulgel (pH 7.4) >> Nurofen® gel > Gel (pH 7.4). From this rank order it was clear that a trend was followed where the pH of formulation also played a role in ibuprofen permeation. All the formulations exhibited a higher release rate and flux when compared to Nurofen® gel. This was statistically significant for the emulgel, gel and Pheroid™ emulgel at pH 7.4. The gel at pH 7.4 exhibited the highest release rate and flux. This was observed for the membrane and skin permeation studies. All the formulations (including Nurofen® gel) presented a correlation coefficient (r2) of 0.972 – 0.995 for membrane permeation studies, and 0.950 – 0.978 for skin permeation studies; indicating that the release of ibuprofen from each of the formulations could be described by the Higuchi model. Furthermore, all the formulations exhibited a prolonged lag time compared to Nurofen® gel which indicated that the ibuprofen was retained for a longer time by the base. This was statistically significant (p < 0.05) for the emulgel at pH 7.4, the gel and Pheroid™ emulgel at pH 5. The gel at pH 7.4 exhibited a lag time closest to that of Nurofen® gel and this difference could not be classified as statistically significant (p > 0.286). This was observed for the membrane and skin permeation studies. Nurofen® gel exhibited the highest ibuprofen concentration in the stratum corneum as well as in the epidermis followed by the gel at pH 7.4. However, results obtained for all the formulations indicated that topical as well as transdermal delivery of ibuprofen was achieved. The pH of a formulation plays an important role with respect to API permeation. Ibuprofen is reported to have a pKa value 4.4 (Dollery, 1999:I1); and by application of the Henderson-Hasselbach equation, at pH 5, 20.08% of ibuprofen will be present in its unionised form and at pH 7.4, 0.1% ibuprofen will exist in its unionised form. Since the unionised form of APIs is more lipid soluble than the ionised form, unionised forms of APIs permeate more readily across the lipid membranes (Surber & Smith, 2000:27). Therefore, it would be expected that ibuprofen formulated at pH 5 would be more permeable than formulations at pH 7.4. However, this did not correspond to the results (membrane studies) obtained in this study. It may be attributed to the solubility of ibuprofen in the different formulations. According to the pH-solubility profile of ibuprofen obtained in this study, it was more soluble at pH 7.4 than at pH 5. This was due to the fact that ibuprofen is a weak acidic compound, and for every 3 units away from the pKa-value, the solubility changes 10-fold (Mahato, 2007:14). However, with regard to the skin permeation studies, enhanced permeation was obtained with the formulations prepared at pH 5. This was in accordance with Corrigan et al., (2003:148) who stated that NSAIDs are less soluble and more permeable at low pH values, and more soluble and less permeable at high pH values. This was most probably due to the fact that unionised species, although possessing a lower aqueous solubility than the ionised species, resulted in enhanced skin permeation due to being more lipid-soluble. Finally, stability tests on the different semi-solid formulations for a period of three months at different temperature and humidity conditions were conducted to determine product stability. The formulations were stored at 25 °C/60% RH (relative humidity), 30 °C/60% RH and 40 °C/75% RH. Stability tests included: mass variation, pH, zeta potential, droplet size, visual appearance, assay, and viscosity. No significant change was observed for mass variation, pH, zeta potential and droplet size over the three months for any of the different formulations stored at the different storage conditions. In addition, no significant change in colour was observed for the gel and emulgel formulations at pH 5 and 7.4 over the three months at all the storage conditions. However, it was observed that the formulations containing Pheroid™ showed a drastic change in colour at all the storage conditions. This might have been due to oxidation of certain components present in the Pheroid™ system. Consequently, further investigation is necessary to find the cause of the discolouration and a method to prevent it. The gel formulated at pH 5 depicted the formation of crystals. This might have been due to the fact that the solubility of ibuprofen was exceeded, leading to it precipitating from the formulation. A possible contributing factor to the varying assay values obtained during the study might have been due to non-homogenous sample withdrawal. On the other hand, no significant change was observed for the emulgel and Pheroid™ emulgel formulated at pH 5 and 7.4. The emulgel and Pheroid™ emulgel formulated at pH 5 depicted relative instability (according to the International Conference on Harmonisation of Technical Requirements For Registration of Pharmaceuticals for Human Use, ICH) only at 40 °C/75% RH with a change in ibuprofen content of more than 5% (6.78 and 6.46%, respectively). The gel, emulgel and Pheroid™ emulgel at pH 7.4 exhibited the least variation in ibuprofen concentration at all of the storage conditions. This might indicate that the pH at which a semi-solid formulation is produced will have a direct influence on the stability of the product. No significant changes in viscosity (%RSD < 5) was observed for the gel and emulgel formulated at pH 7.4 and stored at 25 °C/60% RH. The remaining formulations at all of the specified storage conditions exhibited a significant change in viscosity (%RSD > 5) with a decrease in viscosity being more pronounced at the higher temperature and humidity storage conditions. A possible contributing factor to the change in viscosity over three months at the specified storage conditions might have been due to the use of Pluronic® F-127 (viscosity enhancer). This viscosity enhancer possesses a melting point of approximately 56 °C (BAST Corporation. s.a). The problem with this might have been the temperature (70 °C) at which the formulations were prepared. The higher preparation temperature might have caused the Pluronic® F-127 to degrade, thereby losing its ability to function appropriately. A balance must be maintained between optimum solubility and maximum stability (Pefile & Smith, 1997:148). Despite the lower skin permeation of the gel formulated at pH 7.4, this formulation performed the best, as it was considered stable (least variation during the 3 month stability test) and the obtained tape stripping results showed that this formulation depicted the highest ibuprofen concentrations in the stratum corneum and epidermis. Thus, topical as well as transdermal delivery were obtained. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.