An investigation into the introduction of process analytical technology, using near infrared analysis, to selected pharmaceutical processes
- Authors: Naicker, Krishnaveni
- Date: 2007
- Subjects: Near infrared spectroscopy , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10153 , http://hdl.handle.net/10948/577 , http://hdl.handle.net/10948/d1011710 , Near infrared spectroscopy , Pharmaceutical chemistry
- Description: Introduction: Process analytical technologies are systems for the analysis and control of manufacturing processes to assure acceptable end-product quality. This is achieved by timely measurements of critical parameters and performance attributes of raw material and in-process material and processes. The introduction of process analytical technology using near infrared analysis was investigated in three areas, namely incoming raw material analysis, blend uniformity analysis and moisture determination in the fluid bed dryer. Methodology: Incoming raw material identification - The FOSS XDS rapid content analyzer was used for the development of a NIR method for the identification and material qualification of starch maize and lactose monohydrate. Blend uniformity analysis – The SP15 Laboratory Blender fitted with near infrared probe was utilized for the study. Two types of blend experiments were designed to monitor the distribution of magnesium stearate (lubricant) in the blend, namely, a powder blend utilizing lactose monohydrate and a granule blend utilizing Ridaq® granule. Software methods were developed to monitor the standard deviation of the absorbance at the wavelengths that were specific for lactose monohydrate, Ridaq® granule and magnesium stearate. To confirm the prediction of end-point using near infrared, results were verified using an atomic absorption method for magnesium stearate. The blends were sampled at the selected time intervals corresponding to three states of the blend, namely, before end-point, at end-point and after end-point using a sampling plan. An additional six blends were conducted for the granule blend and sampled when the standard deviation had reached a value below 3 x 10-6 at the magnesium stearate wavelength at four consecutive data points (standard deviation value extrapolated from blends carried out to predetermined time intervals). Moisture determination in the fluid bed dryer – Moisture values for two products (Product A and Product B) were retrospectively collected from past production batches. A process capability study was conducted on the moisture values to determine if the current process was in a state of control. Results and Discussion: Incoming raw material identification – The algorithms used for the spectral library were able to distinguish between the raw materials selected. The spectral library positively identified the starch maize and lactose monohydrate samples that were not present in the library. The negative challenge with pregelatinised starch and tablettose demonstrated that the spectral library was able to differentiate between closely related compounds. Blend uniformity analysis – Blends sampled at the predetermined time intervals demonstrated a homogeneous state when the standard deviation of the absorbance was low and a non-homogeneous state when the standard deviation of the absorbance was high, thus near infrared prediction on the state of the blend was confirmed by the standard analytical methods. The series of Ridaq® granule and magnesium stearate blends sampled when the standard deviation was below 3 x 10-6 were homogeneous with the exception of one blend that was marginally out of specification. Blend durations were significantly lower than the standard blend durations used in the facility and ranged from 112 to 198 seconds. Moisture determination in the fluid bed dryer – From the process capability study of the two products it was noted that Product A is stable but can still be optimized while Product B is at a desirable state. The statistical evaluation of the moisture values for Product A and Product B demonstrated that the use of the product temperature to monitor the moisture gave consistent results. The current process is stable and capable of producing repeatable results although near infrared provides a means for continuously monitoring the product moisture and allows one to take action to prevent over-drying or under-drying. Conclusion: From the investigations conducted, it can be seen that there is definitely a niche for process analytical technology at this pharmaceutical company. The implementation is a gradual process of change, which may take time, probably several years (Heinze & Hansen 2005).
- Full Text:
- Date Issued: 2007
- Authors: Naicker, Krishnaveni
- Date: 2007
- Subjects: Near infrared spectroscopy , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10153 , http://hdl.handle.net/10948/577 , http://hdl.handle.net/10948/d1011710 , Near infrared spectroscopy , Pharmaceutical chemistry
- Description: Introduction: Process analytical technologies are systems for the analysis and control of manufacturing processes to assure acceptable end-product quality. This is achieved by timely measurements of critical parameters and performance attributes of raw material and in-process material and processes. The introduction of process analytical technology using near infrared analysis was investigated in three areas, namely incoming raw material analysis, blend uniformity analysis and moisture determination in the fluid bed dryer. Methodology: Incoming raw material identification - The FOSS XDS rapid content analyzer was used for the development of a NIR method for the identification and material qualification of starch maize and lactose monohydrate. Blend uniformity analysis – The SP15 Laboratory Blender fitted with near infrared probe was utilized for the study. Two types of blend experiments were designed to monitor the distribution of magnesium stearate (lubricant) in the blend, namely, a powder blend utilizing lactose monohydrate and a granule blend utilizing Ridaq® granule. Software methods were developed to monitor the standard deviation of the absorbance at the wavelengths that were specific for lactose monohydrate, Ridaq® granule and magnesium stearate. To confirm the prediction of end-point using near infrared, results were verified using an atomic absorption method for magnesium stearate. The blends were sampled at the selected time intervals corresponding to three states of the blend, namely, before end-point, at end-point and after end-point using a sampling plan. An additional six blends were conducted for the granule blend and sampled when the standard deviation had reached a value below 3 x 10-6 at the magnesium stearate wavelength at four consecutive data points (standard deviation value extrapolated from blends carried out to predetermined time intervals). Moisture determination in the fluid bed dryer – Moisture values for two products (Product A and Product B) were retrospectively collected from past production batches. A process capability study was conducted on the moisture values to determine if the current process was in a state of control. Results and Discussion: Incoming raw material identification – The algorithms used for the spectral library were able to distinguish between the raw materials selected. The spectral library positively identified the starch maize and lactose monohydrate samples that were not present in the library. The negative challenge with pregelatinised starch and tablettose demonstrated that the spectral library was able to differentiate between closely related compounds. Blend uniformity analysis – Blends sampled at the predetermined time intervals demonstrated a homogeneous state when the standard deviation of the absorbance was low and a non-homogeneous state when the standard deviation of the absorbance was high, thus near infrared prediction on the state of the blend was confirmed by the standard analytical methods. The series of Ridaq® granule and magnesium stearate blends sampled when the standard deviation was below 3 x 10-6 were homogeneous with the exception of one blend that was marginally out of specification. Blend durations were significantly lower than the standard blend durations used in the facility and ranged from 112 to 198 seconds. Moisture determination in the fluid bed dryer – From the process capability study of the two products it was noted that Product A is stable but can still be optimized while Product B is at a desirable state. The statistical evaluation of the moisture values for Product A and Product B demonstrated that the use of the product temperature to monitor the moisture gave consistent results. The current process is stable and capable of producing repeatable results although near infrared provides a means for continuously monitoring the product moisture and allows one to take action to prevent over-drying or under-drying. Conclusion: From the investigations conducted, it can be seen that there is definitely a niche for process analytical technology at this pharmaceutical company. The implementation is a gradual process of change, which may take time, probably several years (Heinze & Hansen 2005).
- Full Text:
- Date Issued: 2007
The medicinal chemistry of cyclo (Ser-Ser) and cyclo (Ser-Tyr)
- Authors: Kritzinger, André Louis
- Date: 2007
- Subjects: Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10155 , http://hdl.handle.net/10948/537 , http://hdl.handle.net/10948/d1011712 , Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Description: Cyclic dipeptides are widely used as models for larger peptides because of their simplicity and limited conformational freedom. Some cyclic dipeptides have been shown to produce antiviral, antibiotic and anti-tumour activity (Milne et al., 1998). In this study the cyclic dipeptides, cyclo(Ser-Ser) and cyclo(Ser-Tyr), were synthesised from their corresponding linear precursors using a modified phenolinduced cyclisation procedure. The phenol-induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physicochemical properties of the cyclic dipeptides was achieved by using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. The structures of the synthesised cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modelling. The study aimed to determine the biological activity of cyclo(Ser-Ser) and cyclo(Ser-Tyr) with respect to their anticancer, antimicrobial, haematological and cardiac effects. Anticancer studies revealed that cyclo(Ser-Ser) and cyclo(Ser- Tyr) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Cyclo(Ser-Tyr) exhibited significant activity in the haematological studies, where it increased the rate of calcium induced-coagulation, and decreased the rate of streptokinase-induced fibrinolysis. Both cyclic dipeptides, however, failed to produce any significant effects on thrombin-substrate binding and ADPinduced platelet aggregation. Cardiac studies revealed that cyclo(Ser-Ser) and especially cyclo(Ser-Tyr) reduced the heart rate, coronary flow rate and ventricular pressure of isolated rat hearts.
- Full Text:
- Date Issued: 2007
- Authors: Kritzinger, André Louis
- Date: 2007
- Subjects: Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10155 , http://hdl.handle.net/10948/537 , http://hdl.handle.net/10948/d1011712 , Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Description: Cyclic dipeptides are widely used as models for larger peptides because of their simplicity and limited conformational freedom. Some cyclic dipeptides have been shown to produce antiviral, antibiotic and anti-tumour activity (Milne et al., 1998). In this study the cyclic dipeptides, cyclo(Ser-Ser) and cyclo(Ser-Tyr), were synthesised from their corresponding linear precursors using a modified phenolinduced cyclisation procedure. The phenol-induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physicochemical properties of the cyclic dipeptides was achieved by using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. The structures of the synthesised cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modelling. The study aimed to determine the biological activity of cyclo(Ser-Ser) and cyclo(Ser-Tyr) with respect to their anticancer, antimicrobial, haematological and cardiac effects. Anticancer studies revealed that cyclo(Ser-Ser) and cyclo(Ser- Tyr) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Cyclo(Ser-Tyr) exhibited significant activity in the haematological studies, where it increased the rate of calcium induced-coagulation, and decreased the rate of streptokinase-induced fibrinolysis. Both cyclic dipeptides, however, failed to produce any significant effects on thrombin-substrate binding and ADPinduced platelet aggregation. Cardiac studies revealed that cyclo(Ser-Ser) and especially cyclo(Ser-Tyr) reduced the heart rate, coronary flow rate and ventricular pressure of isolated rat hearts.
- Full Text:
- Date Issued: 2007
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