Assessment of pharma products- thermal analysis Flashcards
Differential Thermal analysis
- DTA involves heating or cooling a test sample and an inert reference under identical conditions, while recording any temperature difference between the sample and reference
- This differential temperature is the plotted against time or against temperature
- Changes in the sample which lead to the absorption or evolution of heat can be detected relative to the inert reference
Thermogravimetric (TG)
-Thermogravimetry is one of the oldest thermal analytical procedures
+Has been used extensivly in the study of polymeic systems
-Involved monitoring the weight loss of the sample in a given atmosphere as a function of temperature
+N2, O2, air, He
+Ambient temp to 1000’C
+Record the first derivative opf the mass loss
TGA
- Load sample
- Sample is surrounded by heated element (furnace)
- Pure gas (oxidsing or inert) is pumped in
- Sample is attached to a sensitive balance
- Monitor change in weight against temperature
Thermogravimetric
Provides information on the bulk composition of compounds
- Oxidation
- Heat resistance
- The amount of water or solvents-bring the temperature just above the solvents boiling point and measure the weight difference (big drop= lots of moisture
- Compositional analysis (mix of 2 or 3 materials)- If there is a large drop in weight at different temperatures this can indicate presence of more than 1 type of matieral in a mix
- Measurement of ash content in a sample- heat material then record the amount of material left behind
Differential scanning calorimetry (DSC)
- We measure the heat that is required to heat the sample and reference pan
- And the difference is plotted as a trace
Summary of pharmaceutically important information derived from thermal analysis
- MPT= -
- Desolvation: Bound and absorbed= + and +
- Glass transition= -
- Heat of transition= -
- Purity determination= -
- Compatibility= +?
- Decomposition kinetics= +
- Polymorphic transition= -
Purity determination of pharmaceuticals
- Assumption: an impurity will depress the MPT of a pure material whose MPT is characterized bvy a MPT (T0) and an Enthalpy of Fusion (⊿H0)
- Impurity range= 0.3-2.0 mole% impurity
- A low DSC purity value is clear evidence that a compound ios not of high purity
- A high purity data by DSC cannot be taken as evidence that the substanve is highly pure without supportive evidence from another analytical technique: HPLC, TLC
- Influence by variables such as scan speed, sample weight and sensitivity
Compatibility studies in formulations
-Importance fo stability studies
Importance fo stability studies
-Requirement for approval by regulatory agencies
-Extensive chemical degradation can lead to a substantial loss of potency
-Degradation products may result in adverse events or be unsafe
-Instability may cause
+Undesirable change in performance e.g. dissolution/bioavailability= poor therapeutic outcome
+Substantial changes in physical apperance of dosage form causing product failures= rejected batches
Compatibility studies in formulation
-Stability studies
-Mix drug with excipient and subject to high temperature and humidity
-Select 2-3 of each class of excipient
+50:50 ratio
+Ratio as found in tablets
+Powder mix
+Granulated
+Compressed
-Assay for drug and degradation products
-Use HPLC, DSC, appearance
Compatibility studies in formulation
-Incompatibility of activities could lead to
+Potency loss
+Complex formation
+Acid/base interactions
+Eutectic mixtures
-Excipients must not react with drug or cause drug to degrade to the extent that the degradation products exceed that given in the specification and which can be justified by toxicology studies
-Real time stability takes 2-5 years so we must be confident that we have selected the correct excipients
Compatibility studies in formulation
-Importance of compatibility studies
-Formulation stability studies are time consuming and expensive
-Need to minimize the number of model formulations
-Provide rational basis for selecting eexcipients used in model formulations
-GOAL: identify excipients that
+are not compatible with the API
+Do not have any impact on the stability of the API
-Assign a relative risk level to each excipient within a functional class
Compatibility studies in formulation
-Excipient screening using DSC
-Rapid response for profiling incompatibility between formulation components
-Interactions between excipients and drugs often result in
+Shifts
+Apperance or disappearance of endothermic or exothermic peaks
-Simple broadening of peaks causing changes in area, onset or peak temperatures are due to mixing of the components
-If interactions occur, then need classical accelerated storage tests
Characterisation of pharmaceutical solids
1) Chemical compound --> Crystal habits OR Internal structures 2) Internal structure --> Amorphous OR crystalline 3) Crystaline --> Polymorphs OR Molecular adducts solvates (Hydrates)
Characterisation of pharmaceutical solids
- Thermal analysis do not show differences between different crystal habits
- Polymorphs may show different MPT, solubilities, chemical reactivities or stability because of different internal oorganisation of molecules (Polymorphs, hydrates, solvates)
- Influence of dissolution behavioiurs and bioavailability by polymorphism
- Evaluation of a new chemical entity (NCE) for polymorphism is important in early preformulaiton studies
Studies of solid dispersions and cyclodextrin complexes
-A dispersion of one or more active ingredients in an inert carrier or matric at the solid state
-Prepared by a melting (Fusion), solvent or melting-solvent method
+Water soluble carriers
+Citric acid
+Sugars
+Urea
+PVP- polyvinylpyrrolidone
+PEG- polyethylene glycol
-Types of solid dispersion
+Solid solutions (eutetics)
+Complexes
+Glass dispersions
-Melt the drug with the polymer and then ensure the process condition minimise recrystalisation meaning the drug is predominantly amorphous
-We then trap the amorphous material within the polymer network this improves the stability issue amorphous drug particles have by minimising exposure to moisture
-Amorphous forms are very unstable because they are so hygroscopic
NB the higher the MW the more viscous the polymer, so in a highly viscous polymers would encapsulate the drugs better than less viscous polymers= more stable
