PHC413 Physical Pharmacy Lecture Week 2 PDF

PHC413 Physical Pharmacy Polymorphism and its clinical implication Associate Professor Dr Nor Amlizan Ramli, RPh  OVERVIEW 1. Definition of polymorphism 2. Pharmaceutical and clinical implications of polymorphis...

PHC413 Physical Pharmacy Polymorphism and its clinical implication Associate Professor Dr Nor Amlizan Ramli, RPh  OVERVIEW 1. Definition of polymorphism 2. Pharmaceutical and clinical implications of polymorphism 1.0 Polymorphism Points to understand 1.0 Polymorphism Compounds: Crystallise out of solution in a variety of different habits depending on the condition of the crystallisation Crystal habits have similar internal structure XRD patterns. Different properties occur - compounds crystallise as different POLYMORPHS. 1.0 Polymorphism It occurs when the molecules rearrange themselves in two or more different ways in the crystal. o Packed differently in the crystal lattice o Differences in the orientation or conformation of the molecules at the lattice site How to detect polymorphism? o X-ray diffraction Analytical Techniques for Solid State Characterisation Powder X-ray Diffractometry (PXRD) – “gold” standard for phase ID – preferred orientation; interference from crystalline excipients Single Crystal XRD – ultimate phase ID within depth understanding of the structure – may be difficult to prepare single crystals Analytical Techniques for Solid State Characterisation Figure: Schematic diagrams of XRD  Analytical Techniques for Solid State Characterisation WHY XRD? Measure the average spacings between layers or rows of atoms Determine the orientation of a single crystal or grain Find the crystal structure of an unknown material Determination of phase compositions, materials properties (texture) Produces 2D diffractogram, liquid or amorphous samples results in continuous and broad peak pattern Distinguishes polymorphs  Analytical Techniques for Solid State Characterisation 95% of all solid materials can be described as crystalline When x-rays interact with a crystalline substance (phase), one gets a diffraction pattern  Analytical Techniques for Solid State Characterisation 1. X-ray diffraction (XRD) n λ=2d sin θ English physicists Sir W.H. Bragg and his son Sir W.L. Bragg developed a relationship in 1913 to explain why the cleavage faces of crystals appear to reflect X-ray beams at certain angles of incidence (theta, θ).  Analytical Techniques for Solid State Characterisation n λ=2d sin θ Variables: d = the distance between atomic layers in a crystal lambda λ = the wavelength of the incident X-ray beam Θ = Bragg’s angles/angles of incidence n = an integer. This observation is an example of X-ray wave interference (Roentgens trahl interferenzen), commonly known as X-ray diffraction (XRD), and was direct evidence for the periodic atomic structure of crystals postulated for several centuries  Analytical Techniques for Solid State Characterisation https://www.youtube.com/watch?v=C1cYJthl BZY Analytical Techniques for Solid State Characterisation Analytical Techniques for Solid State Characterisation Analytical Techniques for Solid State Characterisation  Analytical Techniques for Solid State Characterisation 2. Differential Scanning Calorimetry (DSC) /Modulated DSC (MDSC) - information in phase transition and interaction with excipients – “black box”: no information on the nature of the transition – interference from both crystalline and amorphous excipients  Analytical Techniques for Solid State Characterisation 3. Thermogravimetric Analysis (TGA) – quantitative information on the stoichiometry of solvates/hydrates – interference from water-containing excipients 1.0 Polymorphism Polymorphs possess Different physical and chemical properties Melting point Solubility Different habits – what is habits? External appearance of a crystal - common types? Prismatic Acicular Pyramidal Tabular Equant Columnar Lamellar 1.0 Polymorphism Spironolactone 1.0 Polymorphism Spironolactone 1.0 Polymorphism Paracetamol Figure: SEM structure showing crystal habit of a) Form 1 and b) Form 2 of PCM 1.0 Polymorphism Paracetamol 1.0 Polymorphism Phenobarbitone o Isolated - 8 crystal modification o o Identified with melting points ranging from 112 – 176 C – 11 crystals 1.0 Polymorphism Barbiturates o 70% exhibit polymorphisms 2.0 Pharmaceutical Implications of Polymorphism Problem arises in tableting and injections due to differences in crystal habit. Polymorphs possess different habits – subject to processing problems. Different crystal lattice Different energy contents- influence stability and biopharmaceutical behavior. Polymorphic form with the lowest free energy The most stable Another polymorph will transfer into it 2.0 Pharmaceutical Implications of Polymorphism Figure: Photomicrographs of orthorombic PCM (needles) to monoclinic PCM (prisms and plates). a) t=0 mins, b) t= 30 mins 2.0 Pharmaceutical Implications of Polymorphism 2.0 Pharmaceutical Implications of Polymorphism 2.1 Transformation Transformation between polymorphic form- lead to formulation problem. 2.0 Pharmaceutical Implications of Polymorphism 2.1 Transformation In cream – crystal growth cause grittiness. Theobrama oil – different melting characteristics. In suspension- phase transformation may cause changes in crystal size and caking. 2.0 Pharmaceutical Implications of Polymorphism 2.2 Analytical issues For infra red analytical- carbon shifting may be different In FTIR, sample is blended with KBr to form disc. Changes in spectra due to conversion of crystal – amorphous (eg: digoxin) Changes in crystal form can also be induced by solvent extraction methods for drug isolation from formulations prior to FTIR. Some drug gives different spectra in solid state (eg: cortisone with 7 forms, dexamethasone with 4 forms) 2.0 Pharmaceutical Implications of Polymorphism 2.2 Analytical issues How to overcome? o By converting both samples into the same form by re- crystallisation from the same solvent. 2.0 Pharmaceutical Implications of Polymorphism 2.2 Analytical issues Fourier Transmission InfraRed Spectophotometry 2.0 Pharmaceutical Implications of Polymorphism 2.2 Consequences Possible difference in bioavailability- poorly soluble drug o Dependent upon rate of dissolution o Most stable polymorph – lowest solubility, lower bioavailability. o The differences in bioavailability are usually insignificant. 2.0 Pharmaceutical Implications of Polymorphism 2.2 Consequences Particle size reduction – cause changes in solid properties o Grinding of digoxin may cause formation of amorphous Higher rate of solution – greater activity https://www.youtube.com/watch?v=D6D7HtLqn8Y 2.0 Pharmaceutical Implications of Polymorphism 2.2 Consequences form A- low biological activity – slowly hydrolysed in vivo to free chloramphenicol form B- high biological activity - 7 times greater 2.0 Pharmaceutical Implications of Polymorphism 2.2 Consequences During formulation: Very important to determine polymorphic tendencies of poorly soluble drug. Release profile is correct – for clinical trial o Possible food-drug or drug-drug interaction Toxicity study – physical state of the drug Dosage form development – optimal dosage form is designed.  Clinical Point – Painful Example of Crystallisation Diseases caused by crystal precipitation in the body are often referred to as crystal deposition diseases or crystal-related diseases. These conditions occur when certain substances, such as minerals, salts, or other compounds, accumulate and crystallize within various tissues or organs, leading to inflammation, pain, and damage.  Clinical Point – Painful Example of Crystallisation 1. Gout: Gout is one of the most well-known crystal-related diseases. It occurs when uric acid crystals accumulate in joints, leading to intense pain, inflammation, and swelling, typically in the big toe. High levels of uric acid in the blood can contribute to the formation of these crystals. The uric acid is in needle-like crystals, in the form of monosodium urate. Level of uric acid on the articular cartilage of joints – level of uric Adapted from: https://www.preferredfootankle.com/foot-conditions/gout/ acid exceed a critical solubility level 6.7 mg/dL  Clinical Point – Painful Example of Crystallisation 2. Kidney Stones: Kidney stones are solid, crystalline masses that can form in the kidneys when substances like calcium, oxalate, and uric acid become concentrated and crystallize. These stones can cause severe pain when they pass through the urinary tract. Adapted from: https://www.niddk.nih.gov/health-information/urologic- diseases/kidney-stones/all-content  Clinical Point – Painful Example of Crystallisation 3. Amyloidosis: Amyloidosis is a condition in which abnormal protein deposits called amyloid fibrils can accumulate in various organs, including the heart, kidneys, liver, and nerves. While not crystalline in the same way as other crystals, these protein deposits can disrupt normal organ function. Adapted from: https://amyloidosis.org/facts/al