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Introduction
Recently, thermal analysis has been used extensively in the development and
improvement of pharmaceutical formulations.
Drug purity determination, quantitative and qualitative analysis of formulations,
stability tests, characterization of polymorphic mixtures and drug-excipient
compatibility tests are common experiments.
The photovisual system combines DSC and visual monitoring of physical and chemical
events occurring in the sample during temperature programming.
Decomposition processes involving gas evolution and loss of water necessary for
crystallization can be observed.
This study focuses on propranolol.
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Propranolol is a sympatholytic non-selective beta blocker. Sympatholytics are used to
treat hypertension, anxiety and panic. It was the first successful beta blocker developed.
Propranolol is available in generic form as the hydrochloride.
Brand names Inderal, Inderal LA, Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL,
Sumial, Anaprilinum, Bedranol SR.
Experimental
Sample preparation
Propranolol tablets A and B were bought at local pharmacy.
The following mixture was prepared for DSC analysis:
Propranolol hydrochloride
18.60%
Microcel MC(101)
32.56%
Lactose
13.95%
Starch
27.91%,
PVP
3.26%
Talc
2.32%
Magnesium stearate
1.40%.
For TGA, binary mixtures were prepared by combining porporanolol hydrochloride
with each separate constituents.
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Calorimetric studies
The DSC apparatus was calibrated with indium (156.6±0.2°C) and zinc (419.5±0.3°C)
standard melting points.
The heat flow and enthalpy were calibrated by indium heat of fusion (28.58±0.3 J/g).
DSC curves were obtained in a Shimadzu DSC-50, with nitrogen flow of 50.0 mL/min
and heating rate of 10.0°C/min, up to 500.0°C.
Samples (2.00 mg) were packed in hermetically sealed aluminum cells; an Al cell
was also used as a reference.
The DSC-photovisual system is made of an Olympus microscope connected to a
Sanyo camera, model VCC-D520, with image capture and video recording software.
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Thermogravimetric studies
The TG apparatus was calibrated with calcium oxalate monohydrate.
TGA of binary mixtures and tablets A and B was
performed on a Shimadzu thermobalance, model
TGA-50H, with air flow of 20.0 mL/min, heating rate
of 10.0°C/min, temperature interval of 25.0 to 900.0°C.
The samples (5-5.5 mg) were packed in Al cells.
TG isothermal curves were obtained by plateau of the TG curve before the initial
temperature of decomposition of the drug and tablets A and B.
Samples were heated at a rate of 20.0°C/min up to the isothermal temperature, and the
isothermal temperature was held for 4 h.
Isothermal temperatures varied from 140 to 200°C.
Kinetics
The reaction order (n) was determined by graphical analysis and rate constants
(k) were calculated using the Arrhenius equations.
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Results and discussion
Calorimetric studies (this slide comments on next slide’s flgure)
Pure propranolol hydrochloride showed a melting point at 165.6°C and a heat
of fusion of 137.42 J/g. Around 300oC: probably decomposition.
Lactose alone showed two main peaks: a phase transition and melting 218.9°C.
Propranolol-lactose+others mixture: phase transitions an overlap of traces of
individual compounds, without the transition at 300oC (does lactose prevent
decomposition?)
Tablets A and B showed a lower melting point and heat of fusion (161.9±0.4°C;
3.48 J/g and 161.4°C, 13.10 J/g).
DSC curves showed that tablets A and B had similar formulations and contain
lactose based on the melting peak at 218.4°C. (Also appearing for the mixture).
decomposition?
melting
phase transition
melting
melting of lactose?
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The DSC-photovisual images
Propranolol hydrochloride: melting point at 164°C, followed by volatilization at
169°C.
Lactose: the melting peak at 218°C corresponded to monohydrated α-lactose
form, with a decreased melting point from 223°C due to grinding and compression
during sample preparation. Its decomposition occurred at 236°C.
Propranolol-lactose + others mixture: began melting at 162°C. An intense brown
coloration was observed at 188°C prior to the melting of lactose.
Tablets A and B: melting points occurred simultaneously with the brown
coloration, which was intense at temperatures of 180 and 191°C.
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Conventional DSC did not show significant interaction between propranolol and
lactose.
DSC-photovisual images suggest a typical Maillard reaction* in propranolol.lactose
and tablets A and B.
*Maillard reaction: between amines and reducing sugars. Example:
F. Monajjemzadeh et al., AAPS PharmSciTech. Jun 2009; 10(2): 649–659. Assessment of Feasibility of Maillard Reaction
between Baclofen and Lactose by Liquid Chromatography and Tandem Mass Spectrometry, Application to Preformulation
Studies.
DSC-photovisual showed that propranolol melts, then decomposes and volatilizes.
This did not occur with tablets A and B and binary mixture.
Drug excipients enhance thermal stability propranolol; but chemical reactions may
occur at higher temperatures.
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Thermogravimetric studies: decomposition (for 2 next slides)
Propranolol: two thermal decomposition stages, starting at 252 °C.
Binary mixtures: same decomposition profile as propranolol, with initial mass loss
due to excipients’ humidity.
Starch and lactose reduced the initial temperature of decomposition of propranolol
to 201 and 242.4 °C.
Tablets A and B: similar behaviour as propranolol-lactose binary mixture.
1 PH
2 PH + Mg stearate
3 PH + starch
4 PH + PVP
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1 PH
5 PH + PVP
6 PH + microcel
7 PH + talc
Humidity can alter the stability of solid pharmaceuticals, which may influence the
flow and compression characteristics of powders during the manufacture process
and hardness of final tablets.
TG isothermal curves of drugs presented a decomposition profile similar to that
observed in DSC-photovisual images.
Tablets A and B showed decomposition in two stages that could be explained by
excipient quality/relative amount and by the manufacturing process.
The isothermal data can help differentiate products on the market and establish
quality.
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Kinetics studies
Graphical analysis showed that propranolol decomposed through zero order kinetics
at different temperatures.
Tablets A and B: decomposition by second order kinetics. This suggests interaction
between the drug and some excipients.
Rate constant values revealed that propranolol is more stable than tablets A and B.
Conclusions
DSC-photovisual demonstrated that lactose promotes an interaction when mixed
with propranolol. Lactose was present in commercial tablets.
TG, dynamic and isothermal, showed differences in stability between tablets and
pure drug.
The kinetic parameters confirmed a lower stability for propranolol tablets than
pure propranolol hydrochloride.
Thermal analysis can be adapted for stability studies of pharmaceuticals.
DSC, DSC-photovisual and TG are important in design development
of solid-form pharmaceuticals.
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