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Feasibility of formulating a drug based on molecular formula and crystal…
Feasibility of formulating a drug based on molecular formula and crystal structure
Crystal Structure
Polymorphism - the ability of a substance to exit in two or more crystalline phases with different arrangements and/or conformations
Unit cell - minimal building block (at least one molecule) that forms the repeating building block of the crystal structure
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Arrangement of molecules in space determines polymorph formed
Impact on the properties of the solid
Packing properties
Molar volume and density
Refractive index, optical proerties
Conductivity (electrical and thermal)
Hygroscopicity
Thermodynamic properties
Melting and sublimation temperatures
Internal energy
Enthalpy
Heat capacity
Entropy
Free energy and chemical potential
Thermodynamic activity
Vapour pressure
Solubility
Spectroscopic properties - useful for differentiating between polymorphs
Electronic transitions
Vibrational transitions
Rotational transitions
NMR chemical shifts
Kinetic properties
Dissolution rate
Rates of solid state reactions
Stability
Mechanical properties - greatest impact during formulation
Hardness
Tensile strength
Compactability, tabletability
Handling, flow and blending
Surface properties
Surface free energy
Interfacial tensions
Habit
Probability of formulation of a particular polymorph is dependent on the lattice energy of each of the polymorphs
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Packing is dependant on the favourable intermolecular interactions, the close packing principle and the molecular structure
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Similar molecules may not show similar packing
Internal structure of the crystal
Crystal Habit
Affected by polymorph and unit cell formed
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Affected by crystallisation conditions
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Can provide the basis for different dissolution profiles of a drug, depending on surface area and orientation of the functional groups of the molecule, therefore the interaction with the dissolving solvent
If water miscible functional groups are facing outward this improves aqueous solubility as they are more likely to interact with the fluid
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Alters properties e.g.solubility depending on surface area
The external structure of the crystal
Needle, planar, cuboid, etc
Affects mechanical properties due to change in shape of the crystal
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Easier to predict and control than polymorph
Noyes-Whitney dissolution model predicts dissolution rate taing into account surface area and wettability of the crystal.
DR=dX/dt=(A×D)/h(Cs-X∆/V)
DR = dissolution rate, A = surface area, D = diffusion coefficient, h = thickness of the boundary layer adjacent to the dissolving drug, Cs = saturation solubility, Xd = amount of drug dissolved at time t, V = volume of dissolution media
Water in Crystals
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Solvates - a solvent molecule is incorporated into the unit cell Hydrate - the solvent is water
Formation of a solvate/hydrate may change the properties of the crystal - which could affect bioavailability
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Favourable - improving dissolution or bioavailability
Challenges - formulation and packaging techniques for the final product as may transform to the hydrate in high humidity
Inter-molecular bonds
Packing is specific to the molecule depending on the molecular bonds formed
Hydrogen bonds
Energy landscapes
Kinetic control
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May allow the formation of a metastable polymorph - may have beneficial properties over the thermodynamic global energy minimum
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Local energy minima
May have problems with stability and transforming to the thermodynamically stable form
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Shouldn't if the molecules have limited dynamic motion and there is sufficient difference in lattice energy between this local energy minima and the global energy minima
Specific crystallisation conditions required
Generally show greater solubility, especially with greater difference in lattice energy between polymorphs
Greater aqueous solubility doesn't necessarily correlate to improved absorption and bioavailability
Thermodynamic control
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Gives the global energy minimum
Most stable form is produced, won't change to another polymorph
Favourable in terms of formulatability
Crystals - Repeating units of molecules in three dimensions
Amorphous materials - no long-range order
Some favourable properties
Faster dissolution rates = improved bioavailability?
Molecules not in highly ordered structure so weaker and less consistent intermolecular bonds, allowing for easier disassociation
Reduced chemical and physical stability - may transform into crystalline form on storage
Depends on the mobility of the molecule within the formulation
May alter storage conditions and shelf-life
Lattice energy
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Lower energy is favourable - higher probability the polymorph will form
Determined between the intermolecular forces between molecules in the crystal
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Ideally want polymorphs with a significant difference in lattice energy, resulting in a thermodynamically stable energy minimal product
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Not the case in most crystalline drugs
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Chirality
Alterations in the arrangement of the functional groups in space
May form an alternative unit cell
Heterochiral or homochiral product may be formed - depending on the lattice energy
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May have different properties depending on if hetero- or homochiral. If homochiral may depend on the enantiomer
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Enantiomers may have differing degrees of solvation and crystallisation
May be beneficial in purifying one enantiomer
Molecular Formula
Drug degredation
Hydrolysis
Functional groups such as esters, amides, lactones or lactams
Most commonly encountered due to prevalence of reactive groups and ubiquitous nature of water
Oxidation
Mechanisms complex - removal of an electropositive atom, radical or electron, or addition of an electronegative moiety
Catalysed by oxygen, heavy metals and light --> free radical formation
Aldehydes, alcohols, phenols, alkaloids and unsaturated fats and oils are susceptile
Isomerisation
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Conversion of a molecule into its optical or geometric isomer
May produce different pharmacological or toxilogical profiles
Photolysis
Oxidation-reduction, ring alteration and polymerisation catalysed by exposure to sunlight or artificial light
Lipinski's Rule of Five
Evaluates likelihood of a molecule having chemical and physical properties which make it likely to be an orally active drug
No more than 5 hydrogen bond donors
No more than 10 hydrogen bond acceptors
Molecular mass <500Da
Alternative rules
10 or fewer rotatable bonds
Polar surface area no greater than 140A
Clog P no greater than 5
Over 90% of available drugs are compliant
Biopharmaceutics Drug Disposition Classification System (BDDCS)
Builds on the rule of five and predicts drug disposition characteristics for those meeting and not meeting the requirements
New drugs are frequently high molecular weight, lipophilic, poorly water soluble compounds, usually all falling into BCS class 2
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Limitations to RO5
Only for compound which are not substrates for active transporters
Likely all drugs are substrates for at least one transporter
Come from BCS
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See figure 1 for diagram
https://www.sciencedirect.com/science/article/pii/S0169409X16301491
Class 1 - substrates of transporters but the transporter effects are clinically insignificant. RO5 performs well for these compounds
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Class 2 - extensively metabolised
Classes 3 and 4 drugs would require an uptake transporter in the gut due to poor metabolism and permeability. Once absorbed, these could act as substrates for efflux transporters
RO5 does not perform well, for those that are bioavailable it is assumed the compound is a substrate for a transporter
Based on observations from studies.investigating relevance of transporters, enzymes and the interplay between them
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Quantitative Structure-Property Relationships (QSPR)
Relates physical and chemical properties of compounds to their structures
boiling and melting points, molar heat capacities, heat of vapourisation, density, aqueous solubility, ClogP
Rational determination of properties of new compounds without the need to synthesise and test them
Can complete rapid calculation of thousands of structural descriptors
Mathematical model which connects experimental property values with a set of molecular descriptors
Crystal structure prediction (CSP) and Crystal design
Computational techniques
Evaluating the relative energy of the polymorphs using the electron density distribution of the molecule
Limited to predicting polymorphs of pure crystals, scope for the future of predicting crystal structure for solvates and hydrates
End goal is to predict how a molecule will crystallise
May be used prior to the synthesis to produce desired structural and physical properties
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|Identification of an unanticipated appearance of a new polymorph with differing physical properties
Approaches to prediction vary significantly but have some common steps
Calculating three dimensional molecular structures from the chemical diagrams
usually derived from force field or quantum, mechanic electronic structure calculation
Rigid structures more favourable as less crystal structure possibilities
Searching the crystal packing phase space for the possible crystal packing structures
Often involves calculating and locally minimising lattice energies, with the final energies used to rank the structures
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Assessing the generated structures to rank them in order of likelihood of formation
Usually based on calculated lattice energies
Potential to add lattice dynamics contributions
Crystal design
Producing specific polymorphs
May be able to control the crystallisation process with specific crystallisation conditions to produce a particular polymorph
Determined experimentally currently, in future may be scope to determine crystallisation conditions computationally
Using an aqueous crystallisation fluid may influence arrangement so that hydrophilic functional groups face outwards. This may be favourable in terms of dissolution.
May not correlate with improved absorption and bioavailability
Producing specific crystal habits
As polymorphs, depends on crystallisation conditions
Influences shape by inhibition and enhancement of growth in specific directions depending on interaction between the drug molecule and the crystallising solvent
Co-Crystals
Multicomponent crystalline solids composed of an API alongside one or more pharmaceutically acceptable molecules known as the pharmaceutical cocrystal former (coformer
Purpose is to modify or generate particular physicochemical properties of the API solid form.
Design is largely based on reliable patterns of directional non-covalent intermolecular bonds e.g. hydrogen bonds
Important functional groups in co-crystal design are frequently found in pharmalogically active molecules
Exhibit polymorphism
May be able to influence the polymorph formed
Able to exhibit different co-crystals depending on the stoichiometric ratio between API and coformer
Do not represent different metastable forms, unable to change from one form to a thermodynamically stable form like kinetically metastable polymorphs
Able to increase (or reduce) the solubility of an API
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Altering the solid-state arrangement of molecules controls the intrinsic mechanical properties of the solid
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Increase tensile strength
Determines differences between enantiomers
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Formulation
Stability and shelf-life
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Reduced stability results in a shorter shelf-life and/or more difficult storage conditions, limiting marketability and patient acceptability
Dissolution profile
Influenced in part by particle size
Micronised particles (<10nm) have much faster dissolution due to a greater surface area
Micronisation unfavourable as reduces physical and chemical stability and gives electrostatic tendencies, affecting mechanical properties
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Small particles can be produced during the crystallisation process
Have a tendency to aggregate and form dense particles in dissolution medium
Most beneficial to form a porous agglomerate where dissolution medium can penetrate and allows fast dissolution
Can be done by spherical agglomeration (SA) or emulsion solvent diffusion (ESD)
Considered rapidly dissolving when no less than 85% of the drug substance dissolves within 30 mins at 100 rpm in a volume of 900ml or less in each medium
Biopharmaceutical Classification System (BCS)
Experimental model which measures permeability and solubility under prescribed conditions
http://www.particlesciences.com/news/technical-briefs/2011/biopharmaceutical-classification-system.html
See Figure 1 for diagram
For class 1 molecules, the formulation is straightforward, and essentially may consist of the neat API and some filler excipients
Other classes produce challenges for formulation, and the BCS can be used to guide delivery system design, depending on the route of administration
It is assumed that class 1 drugs in rapidly dissolving drug products will be bioequivalent, and dissolution data can be used as a surrogate for pharmacokinetic data to demonstrate bioequivalence
Reduces cost of approving, scale-up and post-approval changes for oral drug products, without compromising safety
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Considered highly soluble when the higher clinical dose is soluble in 250ml or less of aqueous media between pH of 1-7.5 at 37 degrees
Minimum of 3 replicates at each pH
Determination of permeability
Pharmacokinetic studies in human subjects including mass balance studies, and absolute bioavailability studies, or intestinal permeability methods
In vivo
or
in situ
intestinal perfusion in a suitable animal model
In vitro
permeability methods using excised intestinal tissues
Monolayers of suitable epithelial cells e.g. Caco-2 cells or TC-7 cells
Considered highly permeable when the extent of absorption in humans is 90% or more of an administered dose based on mass balance determination or in comparison to an IV reference dose
Accounts for potency in that solubility and permeability are relative to clinical dose
Poor solubility is the most common theme
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J = PwCw
J = flux across gut wall, Pw = permeability of gut wall, Cw = concentration profile at gut wall
Dosage forms
Solid oral dosage forms are generally the preferred option
May be prevented by physiological and physicochemical mechanisms so alternative such as suspensions or solutions are explored
Targets may dictate which dosage form to use, the physical properties of the drug still dictate how successful this will be, and this can be determined by BCS
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Many factors must be considered in addition to BCS class when formulating
Solubility profile
Polymorph status
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Desired dosage form
Target dose and dosage regimen
Drug stability
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Excipient compatibility
Knowledge of transporter and metabolic pathways
Non-technical factors
Cost
Intellectual property
Distribution chain limitations
Interactions with excipients
Excipient included to aid manufacture, administration and absorption of the API
Considered pharmacologially inert generally, but depending on the nature of the drug may propogate or participate in chemical or physical reactions with the drug molecule
May compromise effectiveness
Purposes of excipients
Improvement of the stability of the API
Modulation of bioavailability of API
Maintain pH of liquid formulation
Maintain rheology of semisolid dosage form
Act as a binder or disintegrant
Act as an antioxidant or emulsifying agent
Allows adequate administration
Facilitates manufacturing
Aesthetics
Identification
Types of excipients include: binders, disintegrants, fillers (diluents), lubricants, glidants, compression aids, colours, sweeteners, preservatives, flavours, film-formers/coatings, suspending/dispersing agents/surfactants
Physical interactions
Frequently used in manufacturing to modify drug dissolution - may be beneficial or detrimental
Interactive mixing
Smaller particles (API) interacts with surface of larger molecules (excipients) through physical forces. API dissolves or surface interactions change in GIT to allow release
Adsorption of drug onto excipients may prevent the API from being able to dissolve and diffuse, reducing bioavailability
Generally occur at the surface of crystalline drugs where reactive functional groups may come into contact with one another
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Water can be adsorbed easily at crystal defects which can trigger drug-excipient interactions
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Chemical interactions
Chemical reaction between API and excipient/s and/or impurities which forms different molecules
Usually detrimental as form degradation products
e.g. primary amines with glycosidic hydroxyl groups and double bonds, secondary amines with reducing sugars
Poorly water soluble drugs
pH adjustment
pH affects degree of ionisation. When ionised a drug generally has a higher solubility than its neutral form
Drugs are generally neutral at physiological pH
Buffering excipients control pH of micro environment around drug molecule
Final pH is selected not only according to drug solubility, but considering tolerance, bioavailability, efficacy and stability
Prodrug design
Inactive, chemically modified version of a parent drug
Improves physico-chemical properties
Carrier linked prodrugs where parent drug is covalently linked to a prodrug moiety
Bioprecursor prodrugs - modified parent drug with functional groups requiring hydration or redox reactions
Small drug particles
Increase surface area and dissolution rate
Affects manufacturing process
Co-solvents
A water miscible organic solvent used to increase solubility of a drug in water
Dissolution is enhanced when the solute and solvent have similar physicochemical properties
most important consideration is polarity of the mixture and dielectric constant
Ethanol, PEG, DMSO
Limitations
Taste
Stability
Adverse physiological effects
Potential modification of pharmacokinetic profile of the drug
Surfactants and lipids
Surfactant - surface-active agent which stabilises interfaces
Micelles - hydrophilic spherical shells with a hydrophobic head and hydrophilic core. Core creates a suitable environment to solubilise lipophilic drugs
Liposomes - globular bilayer formations. Solubilisation of lipophilic drugs in the bilayer
Emulsions - dispersions of two imimiscible phases stabilised by surfactant