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An ab initio study of ion solvation in waterHeuft, Jasper Martijn. January 1900 (has links)
Proefschrift Universiteit van Amsterdam. / Met een samenvatting in het Nederlands. - Lit. opg.
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The effect of soluble and insoluble fillers/binders on the disintegration and dissolution of drugs from directly compressed tablet formulations / Annelize KlynsmithKlynsmith, Annelize January 2002 (has links)
Although disintegration is not always a prerequisite for drug dissolution, this process
plays a significant role in the rate and extent of dissolution, especially in the case of
sparingly water-soluble drugs (like furosemide). Any factor that influences tablet
disintegration, therefore, will influence drug dissolution. Since the filler often
comprises more than 80% of the total tablet weight, it will affect tablet properties and
therefore disintegration. The solubility of the filler is expected to play a major role in
determining tablet disintegration.
During the initial stage of the study the physical powder properties (density, particle
size, flow properties and compressibility) of Tablettose® (soluble) and Avicel® PH 200
(insoluble) as tablet fillers were determined and compared in order to establish their
inherent powder properties.
Tablets from mixtures containing each filler and 0.5% w/w magnesium stearate (as
lubricant) were prepared at a constant die fill volume at different compression
pressures. Since Tablettose® could not be tableted without a lubricant due to high
friction during ejection, magnesium stearate was included in all formulations. Tablets
were evaluated in terms of weight variation, crushing strength, friability and
disintegration times. Tablettose® produced tablets with extremely low crushing
strengths and high friability compared to Avicel® PH 200, which produced tablets with
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acceptable physical properties. The most significant difference between the two
formulations was observed in the disintegration times, with the Avicel® tablets
producing rapid disintegration whilst Tablettose® produced slowly dissolving rather
than disintegrating tablets. These results indicated shortcomings in the properties of
Tablettose® as directly compressible filler and suggested possible problems in terms
of drug release.
Following the results from the previous experiments, the effect of addition of 3.5, 5
and 7% w/w Kollidon® 30 and Kollidon® VA 64 as dry binder (to increase mechanical
strength) and 0.5, 1 and 2% w/w Ac-Di-Sol®, Kollidon® CL and sodium starch glycolate as disintegrant (to induce tablet disintegration) on the physical properties of
Tablettose® formulations was evaluated in order to eliminate the observed poor
physical tablet properties. Although the presence of a dry binder had little effect on
the crushing strength of the tablets it did increase the compression range during
tableting, thereby increasing the compression force before capping occurred.
Kollidon® VA 64 (3.5%) proved to be the most efficient. The incorporation of a
disintegrant, irrespective of the type or concentration of the disintegrant, resulted in a
significant decrease in disintegration time (1 % of each disintegrant provided efficient
disintegration). This was ascribed to a change from slowly dissolving tablets (with
disintegration exceeding 15 minutes) to rapidly disintegrating tablets (with
disintegration times less than 3 minutes).
In the final stage the dissolution of furosemide (chosen as model drug representing
sparingly water-soluble drugs for which dissolution is the rate-limiting step) from
Avicel®, Tablettose® and Tablettose®/Kollidon® VA 64 and Ac-Di-Sol®, Kollidon® CL
or sodium starch glycolate formulations was determined in 0.1 M HCI. Dissolution
results were compared using calculated dissolution parameters, namely the initial
dissolution rate (DRi) and the extent of dissolution (AUC). Dissolution from the
slowly dissolving Tablettose® tablets was significantly slower compared to the rapid
disintegrating Avicel® tablets, confirming the hypothesis that slowly dissolving (but
non-disintegrating) formulations impede drug dissolution due to the small surfacearea
of the drug exposed to the surrounding medium. The incorporation of Kollidon®
VA 64 (as dry binder) in Tablettose® formulations resulted in unexpectedly high drug
dissolution comparable with profiles obtained from the Avicel® tablets, despite the
fact that the tablets did not disintegrate. The literature provided an answer, indicating
that Kollidon® VA 64 increased the solubility of furosemide (Buhler, 1993:114),
possibly due to the formation of a drug/excipient complex. Addition of a disintegrant
to this formulation further increased drug dissolution due to rapid tablet disintegration.
Once again no significant difference in drug dissolution was observed between the
three disintegrants used. The dissolution results also indicate a dependency of the
extent of drug dissolution (AUC) on the initial dissolution rate (DRi), indicating the
importance (although not an absolute prerequisite) of establishment of rapid contact
between drug particles and the surrounding medium through the incorporation of a
disintegrant. / Thesis (M.Sc.(Pharm.))--Potchefstroom University for Christian Higher Education, 2002
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The effect of soluble and insoluble fillers/binders on the disintegration and dissolution of drugs from directly compressed tablet formulations / Annelize KlynsmithKlynsmith, Annelize January 2002 (has links)
Although disintegration is not always a prerequisite for drug dissolution, this process
plays a significant role in the rate and extent of dissolution, especially in the case of
sparingly water-soluble drugs (like furosemide). Any factor that influences tablet
disintegration, therefore, will influence drug dissolution. Since the filler often
comprises more than 80% of the total tablet weight, it will affect tablet properties and
therefore disintegration. The solubility of the filler is expected to play a major role in
determining tablet disintegration.
During the initial stage of the study the physical powder properties (density, particle
size, flow properties and compressibility) of Tablettose® (soluble) and Avicel® PH 200
(insoluble) as tablet fillers were determined and compared in order to establish their
inherent powder properties.
Tablets from mixtures containing each filler and 0.5% w/w magnesium stearate (as
lubricant) were prepared at a constant die fill volume at different compression
pressures. Since Tablettose® could not be tableted without a lubricant due to high
friction during ejection, magnesium stearate was included in all formulations. Tablets
were evaluated in terms of weight variation, crushing strength, friability and
disintegration times. Tablettose® produced tablets with extremely low crushing
strengths and high friability compared to Avicel® PH 200, which produced tablets with
-
acceptable physical properties. The most significant difference between the two
formulations was observed in the disintegration times, with the Avicel® tablets
producing rapid disintegration whilst Tablettose® produced slowly dissolving rather
than disintegrating tablets. These results indicated shortcomings in the properties of
Tablettose® as directly compressible filler and suggested possible problems in terms
of drug release.
Following the results from the previous experiments, the effect of addition of 3.5, 5
and 7% w/w Kollidon® 30 and Kollidon® VA 64 as dry binder (to increase mechanical
strength) and 0.5, 1 and 2% w/w Ac-Di-Sol®, Kollidon® CL and sodium starch glycolate as disintegrant (to induce tablet disintegration) on the physical properties of
Tablettose® formulations was evaluated in order to eliminate the observed poor
physical tablet properties. Although the presence of a dry binder had little effect on
the crushing strength of the tablets it did increase the compression range during
tableting, thereby increasing the compression force before capping occurred.
Kollidon® VA 64 (3.5%) proved to be the most efficient. The incorporation of a
disintegrant, irrespective of the type or concentration of the disintegrant, resulted in a
significant decrease in disintegration time (1 % of each disintegrant provided efficient
disintegration). This was ascribed to a change from slowly dissolving tablets (with
disintegration exceeding 15 minutes) to rapidly disintegrating tablets (with
disintegration times less than 3 minutes).
In the final stage the dissolution of furosemide (chosen as model drug representing
sparingly water-soluble drugs for which dissolution is the rate-limiting step) from
Avicel®, Tablettose® and Tablettose®/Kollidon® VA 64 and Ac-Di-Sol®, Kollidon® CL
or sodium starch glycolate formulations was determined in 0.1 M HCI. Dissolution
results were compared using calculated dissolution parameters, namely the initial
dissolution rate (DRi) and the extent of dissolution (AUC). Dissolution from the
slowly dissolving Tablettose® tablets was significantly slower compared to the rapid
disintegrating Avicel® tablets, confirming the hypothesis that slowly dissolving (but
non-disintegrating) formulations impede drug dissolution due to the small surfacearea
of the drug exposed to the surrounding medium. The incorporation of Kollidon®
VA 64 (as dry binder) in Tablettose® formulations resulted in unexpectedly high drug
dissolution comparable with profiles obtained from the Avicel® tablets, despite the
fact that the tablets did not disintegrate. The literature provided an answer, indicating
that Kollidon® VA 64 increased the solubility of furosemide (Buhler, 1993:114),
possibly due to the formation of a drug/excipient complex. Addition of a disintegrant
to this formulation further increased drug dissolution due to rapid tablet disintegration.
Once again no significant difference in drug dissolution was observed between the
three disintegrants used. The dissolution results also indicate a dependency of the
extent of drug dissolution (AUC) on the initial dissolution rate (DRi), indicating the
importance (although not an absolute prerequisite) of establishment of rapid contact
between drug particles and the surrounding medium through the incorporation of a
disintegrant. / Thesis (M.Sc.(Pharm.))--Potchefstroom University for Christian Higher Education, 2002
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Ion solvation in water femtosecond spectroscopy of hydrogen-bond dynamics /Kropman, Michel François. January 2004 (has links)
Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.
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Dissolution at porous interfacesGrijseels, Hans, January 1900 (has links)
Thesis (doctoral)--Rijksuniversiteit te Utrecht, 1983. / Summary and vita in Dutch. Includes bibliographical references.
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The physico-chemical properties of spiramycin and clarithromycin / Rodé van EedenVan Eeden, Rodé January 2012 (has links)
In most cases, organic materials exist in the solid phase as polymorphs, solvatomorphs or
amorphous forms. Physico-chemical properties in the solid-state are all affected primarily in
terms of dissolution, solubility, bioavailability, stability and processability. Therefore
investigation into the polymorphic behaviour of APIs has become a mandatory part of drug
characterisation studies by pharmaceutical companies (Giron, 2001).
The influence polymorphism has on bioavailability and the need for the development of
drugs in the amorphous form have instigated regulatory bodies such as the FDA to require
solid-state characterisation of pharmaceuticals (Strachan et al., 2005). Subsequently a
study was conducted to determine the physico-chemical properties of two poorly watersoluble
macrolides; clarithromycin and spiramycin. Characterisation methods included:
XRPD, IR, TGA, DSC, SEM, Karl Fischer titration, solubility and stability studies.
Recrystallisations of spiramycin from various solvents indicated that this API mainly exists in
the amorphous form. The DSC proved to be of little value in the characterisation of this
particular macromolecular antibiotic, since wide inter-sample variations were mostly
obtained. TGA results showed higher solvent uptake than expected. This was ascribed to
the amorphous, sponge-like character of this drug.
For the sake of reproducibility and quality of the results, characterisation of spiramycin was
more reliant on spectroscopic and crystallographic methods. Samples generated from 2-
butanol, chloroform, ethyl acetate, 1.4-dioxane, methanol, n-propanol, iso-propanol and
tetrahydrofuran showed characteristic peaks in the range of 2000-2400 cm-1 that were not
present in the IR spectrum of the raw material. Conversely, the XRPD patterns were all identical, exhibiting a characteristic “halo” pattern with no detectable Bragg diffraction peaks.
A solubility assessment showed no significant differences between the raw material and the
recrystallisation products. In fact the raw material seemed to be the form with the highest
solubility, albeit it only by a small margin.
According to the literature, clarithromycin exists in five forms. Form 0 exists as a solvate,
form I is a metastable form, form II is the stable form (Liu & Riley 1998; Deshpande et al.,
2006), form III is a solvate of acetonitrile (Liu et al., 2003; Liang & Yao, 2008) and form IV is
a hydrate (Avrutov et al., 2003). The stable form II is used in formulations currently on the
market.
A follow-up study was done relating to a study performed by De Jager (2005). The raw
material (form II) was recrystallised from acetonitrile, chloroform and ethyl acetate.
Two new crystal forms were prepared from chloroform and acetonitrile. With the necessary
driving force, both of these crystals forms are able to convert to the thermodynamically
stable form II. In addition, a solvate recrystallised from chloroform together with its
corresponding desolvate, showed a 4 and 1.5 fold respective increase in solubility when
compared to the raw material.
The recrystallisations from ethyl acetate delivered crystals with an XRPD pattern similar to
form II. This proved that clarithromycin can be recrystallised directly from this solvent
without the need of an additional conversion step, as was the case in the study done by De
Jager (2005). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2013
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The physico-chemical properties of spiramycin and clarithromycin / Rodé van EedenVan Eeden, Rodé January 2012 (has links)
In most cases, organic materials exist in the solid phase as polymorphs, solvatomorphs or
amorphous forms. Physico-chemical properties in the solid-state are all affected primarily in
terms of dissolution, solubility, bioavailability, stability and processability. Therefore
investigation into the polymorphic behaviour of APIs has become a mandatory part of drug
characterisation studies by pharmaceutical companies (Giron, 2001).
The influence polymorphism has on bioavailability and the need for the development of
drugs in the amorphous form have instigated regulatory bodies such as the FDA to require
solid-state characterisation of pharmaceuticals (Strachan et al., 2005). Subsequently a
study was conducted to determine the physico-chemical properties of two poorly watersoluble
macrolides; clarithromycin and spiramycin. Characterisation methods included:
XRPD, IR, TGA, DSC, SEM, Karl Fischer titration, solubility and stability studies.
Recrystallisations of spiramycin from various solvents indicated that this API mainly exists in
the amorphous form. The DSC proved to be of little value in the characterisation of this
particular macromolecular antibiotic, since wide inter-sample variations were mostly
obtained. TGA results showed higher solvent uptake than expected. This was ascribed to
the amorphous, sponge-like character of this drug.
For the sake of reproducibility and quality of the results, characterisation of spiramycin was
more reliant on spectroscopic and crystallographic methods. Samples generated from 2-
butanol, chloroform, ethyl acetate, 1.4-dioxane, methanol, n-propanol, iso-propanol and
tetrahydrofuran showed characteristic peaks in the range of 2000-2400 cm-1 that were not
present in the IR spectrum of the raw material. Conversely, the XRPD patterns were all identical, exhibiting a characteristic “halo” pattern with no detectable Bragg diffraction peaks.
A solubility assessment showed no significant differences between the raw material and the
recrystallisation products. In fact the raw material seemed to be the form with the highest
solubility, albeit it only by a small margin.
According to the literature, clarithromycin exists in five forms. Form 0 exists as a solvate,
form I is a metastable form, form II is the stable form (Liu & Riley 1998; Deshpande et al.,
2006), form III is a solvate of acetonitrile (Liu et al., 2003; Liang & Yao, 2008) and form IV is
a hydrate (Avrutov et al., 2003). The stable form II is used in formulations currently on the
market.
A follow-up study was done relating to a study performed by De Jager (2005). The raw
material (form II) was recrystallised from acetonitrile, chloroform and ethyl acetate.
Two new crystal forms were prepared from chloroform and acetonitrile. With the necessary
driving force, both of these crystals forms are able to convert to the thermodynamically
stable form II. In addition, a solvate recrystallised from chloroform together with its
corresponding desolvate, showed a 4 and 1.5 fold respective increase in solubility when
compared to the raw material.
The recrystallisations from ethyl acetate delivered crystals with an XRPD pattern similar to
form II. This proved that clarithromycin can be recrystallised directly from this solvent
without the need of an additional conversion step, as was the case in the study done by De
Jager (2005). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2013
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Influence of selected formulation factors on the transdermal delivery of ibuprofen / Aysha Bibi Moosa.Moosa, Aysha Bibi January 2012 (has links)
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.
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Influence of selected formulation factors on the transdermal delivery of ibuprofen / Aysha Bibi Moosa.Moosa, Aysha Bibi January 2012 (has links)
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.
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Properties and use of SO2 for the hybrid sulfur process / Krüger A.J.Krüger, Andries Johannes. January 2011 (has links)
Thematic interrelation is an underdeveloped field of inquiry in Lukan studies. The
design and elegance of Lukan theology begs for guided investigation into a possible
system of organisation that governs history and theology, that is, narrative and theme.
Based on the Greimasian Actantial Model, morpho–syntactical structural–critical
analysis of Luke and Acts reveals that the covenant concept in its operative aspect of
service functions as an organising principle, structuring the narratives and facilitating
thematic interrelation.
A survey of representative Lukan research consisting of five methodologically
determined approaches shows a commonality regarding Lukan purpose. These all share
the “plan of God” as a fundamental concept, thus intimating its plausibility as a
common organisational principle in the text. This observation encourages further
analysis of Lukan narrative and meta–narrative as relevant subject matter.
Investigation into the purpose and goals of Ancient Jewish and Ancient Greek literature
suggests that the concepts of piety/holiness and justness combined with a notion of
divine order and expectation demonstrates organisational capacity.
Under the terms and conditions of the Old Covenant three non–exclusive
themes/concepts hold organisational functionality and ability to facilitate thematic
interrelation: Exodus typology, the covenant concept and the eschaton idea. Exodus
typology connects narrative with theme, developing Israel’s story. The covenant idea
frames stories using parallelism and gives the meta–story progression. The eschaton
idea presents the Day of YHWH as an organisational principle guiding the story of
judgment to restoration. It is observed that the covenant concept is the most prevalent
of these themes/ideas.
Assuming the conceptual unity of Luke and Acts and adopting a morpho–syntactical
structuralist approach, it was observed that the covenant concept in its operative aspect
of service occurred as Helper at ten places, determining the development and structure
of the meta–narrative. According to the Greimasian Actantial Model, Israel failed to
fulfil its covenant–based mandate to serve God and shine God’s light of mercy to the
nations. Jesus, Israel’s new Helper, becomes the Subject and by his covenant–based
ministry, characterised as the greatest service, resolves the problem that prevents Israel
from carrying out its divine mandate and sets the stage for its fulfilment. In Jesus Israel
is given new leaders, an ethical platform of discipleship and the Holy Spirit. The
apostle Paul as the epitomised and exemplary witness and servant of Jesus fulfils what
Israel could not. He is vindicated in righteousness and shares in the Isaianic ministry of
Jesus, to bear witness to leaders and to shine God’s light to the nations. Paul is
unhindered in this ministry. Additionally, in thematic–critical terms, the key placement
of the covenant concept in its operative aspect of service at plot–defining junctures
features its catalytic dynamic as a “template” concept advancing the re–conceptualising
of themes and providing a platform for meaningful relation.
The evidence thus suggests that the covenant concept in its operative aspect structures
the conjoined narratives of Luke and Acts. It also provides a basis for relation between
the divine and humans in the context of the history of God’s salvation, linking history
and theology, and makes possible a discernible means to thematic interrelation.
The SO2 electrolysis was performed by supplying the anode of the cell with SO2 gas, while the water was fed to the cathode using graphite plates as flow fields. Initial experimental work was done at ambient pressures on the anode (SO2 gas–fed) and cathode (water–fed) after which the water pressure was increased from ambient to 1 bar. Various parameters were evaluated for SO2 electrolysis at ambient conditions, including operating temperature, membrane thickness and catalyst loading. The operating temperature was increased from 50oC to 80oC which resulted in a significant voltage improvement from 0.78V to 0.64V at 300mA/cm2. Operating the cell with thinner membranes (86 vs 170um) also resulted in an improved overall cell performance, while the catalyst loading (1 vs 0.5mgPt/cm2) had a negligible effect on the operating voltage. SEM images and EDX analysis were performed on the best performing MEA (N1135) which showed that no degradation of the MEA had occurred. / Thesis (M.Sc. (Chemistry))--North-West University, Potchefstroom Campus, 2011.
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