Amorphous Drug Formulations and Analysis

State features of the Noyes-Whitney equation

dC/dt = DA/h(Cs-C). All of the drug must dissolve for dissolution to occur (important for oral dosage forms, doesn't really apply to parenteral injections).

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State features of drug dissolution

Drug molecule needs to reach the active site to work. Oral drug must be dissolved to be absorbed. The main issue is that drugs are not very soluble but have good permeability

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What is the BCS?

Class I (high permeability, high solubility). Class II (high permeability, low solubility - most drugs). Class III (low permeability, high solubility). Class IV (low permeability, low solubility)

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What are the strategies to improve drug dissolution?

Salt formation, solubilisation, particle size reduction, solid dispersion, encapsulation, amorphous

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Describe features of salt formation

For weakly acidic drug, increase local pH in diffusion layer to increase the value of Cs, ionisation state (pKa and pH) - affects dissolution

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State features of the GI tract

pH of digestive system various a lot, pH also depends on the person, food, time of the day

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State features of solubilisation

Use of surfactants, formation of micelles with hydrophobic cores, for water-soluble drugs

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State features of particle size reduction

Milling, may need wetting agents, increase specific surface area, need to consider impact of milling on stability of drug (e.g. heat energy from milling), if particle size is too small (issues with statics and flowability), trapped air (issues with surfac

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State features of solid dispersion

Insoluble drug dispersed in water soluble matrix, homogenously dispersed, water soluble matrix able to dissolve in environment and expose the drug

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State features of encapsulation

Cyclodextrin, hydrophobic core, drug encapsulated, outside of cyclodextrin have hydrophilic functional groups, encapsulated drug will dissolve more

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State features of amorphous

In a crystalline material (long-range ordered manner, strong intermolecular attractions, high energy required to break lattice), amorphous (easier dissolution)

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What are the limitations of the strategies to improve drug dissolution? (1)

Salt formation – may not be possible, may reconvert into aggregates of low solubility form (disproportionation). Solubilisation – need to use organic solvent or surfactants

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What are the limitations of the strategies to improve drug dissolution? (2)

Particle size reduction – practical limit to size reduction, increased difficulties on handling. Solid dispersion – require novel preparation methods

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What are the limitations of the strategies to improve drug dissolution? (3)

Encapsulation – require to find or develop suitable molecules. Amorphous – thermodynamically unstable

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Describe features of amorphous preparations

Amorphous preparations. Small scale lab-based techniques, quenching cooling, mechanical activation (ball milling). Holt melt extrusion. Supercritical fluid impregnation. (Spray drying).(Freeze drying)

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What is quench cooling?

Melting of drug to create disordered structure. Molten drug is cooled rapidly to maintain the disordered structure. Not suitable for heat sensitive drug

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What is ball milling? (1)

Crystalline drugs are impacted between hard surfaces which breaks the crystalline structure. Local heating from the impact can also help the formation of amorphous materials. Ball milling may not achieve 100% conversion and it can take a long time to mill

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What is ball milling? (2)

Drug recovery could be low because of sticking of drug to impact surfaces.
Slow process. Disruption of crystal lattice by the mean of force (milling) can create amorphous regions

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What is hot-melt extrusion?

Feed into extruder drug and excipient. Blend together at elevated temperature. Sheared rapidly in screw. Production of homogenous mixture. Granulated pellets produced. Advantages – able to scale up. Disadvantages – not suitable for heat sensitive drugs or

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What is a supercritical fluid? (1)

Solid to liquid – melting. Liquid to gas – evaporation. As pressure increases, boiling points stops at a certain point. At a certain pressure, there is no boiling point – SCF region (no distinction between liquid and gas). Supercritical fluid impregnation

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What is a supercritical fluid? (2)

SCF drug in polymer matrix, CO2 can break into polymer, remove solvent, drug molecule will be impregnated in polymer matrix, drug is highly soluble in fluid (diffusion). Partitioning – drug is poorly soluble in fluid but can be trapped in polymer matrix

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What is polymorphism?

Solid material with at least two different molecular arrangements that give distinct crystal species

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Describe features of polymorphism (1)

Different polymorphs can change physical properties – melting point, density, crystal shape, vapour pressure, optical and electrical properties
High melting species are the most stable form
Other polymorphs are metastable and will eventually convert to t

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Describe features of polymorphism (2)

Structure - more spaced out (lower density). Would break easily (natural break lines). Easier to remove molecules (lower mp, higher solubility, dissolves more rapidly). More compact (higher density). No obvious break lines.

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Describe features of polymorphism (3)

More interwoven into structure (higher mp, lower solubility, dissolves more slowly)

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Describe features of glass transition temperature (1)

A characteristic temperature at which there is a major change in properties. Below Tg - brittle glassy state, lack mobility, more stable (takes longer to convert into crystalline state)

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Describe features of glass transition temperature (2)

Above Tg - rubbery state, increased mobility, less stable (more rapid conversion to crystaline form)

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Describe features of glass transition temperature (3)

Tg may be lowered by the addition of a plasticizer (e.g. water or CO2 molecules). Amorphous materials often absorb more water than their crystalline counter part and more easily plasticised by water

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Describe features of glass transition temperature (4)

Note that apart from Tg, temperature and humidity can also degrade the drug through oxidation and hydrolysis (store in cool and dry place)

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Describe vibrational spectroscopy (1)

Molecules vibrate, even at absolute zero. Molecular vibration give rise to well defined energy levels depending on the bond strength (length) and the mass of the system. Measurement of transitions between these energy levels provide an insight into the mo

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Describe vibrational spectroscopy (2)

Depends on strength of bond. Mass and strength. Frequency of vibration is proportional to square root of k/m. Mass higher – lower frequency. High constant – higher frequency. Indicates molecular state of molecule, crystalline or amorphous

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Describe features of Raman scattering (1)

Measurement of inelastic scattering effect to probe vibrational energy levels. Measurement of inelastic scattering effect to probe vibrational energy levels. Sensitivity is poor, inherently weak process. Raman intensity equation.

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Describe features of Raman scattering (2)

Improve sensitivity – increase power of source, use shorter excitation wavelength (risk of fluorescence), longer exposure time, use enhancement methods (resonance Rama), surface enhanced Rama, non-linear Raman

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What are the common obstacles? (1)

Unwanted fluorescence – quenching (use suitable solvent to quench signal), photo bleaching (burn off impurities that fluoresce), Kerr gate (utilize difference in relaxation time).

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What are the common obstacles? (2)

Photo or thermal damage of samples: use lower power, use excitation wavelength outside absorption region of samples

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State features of Raman vs IR (1)

Same information – vibrational transitions, functional group analysis. Different selection rules – IR (dipole), Raman (polarizability), IR (cannot measure through water or glass but Raman can). Raman spectra are single beam.

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State features of Raman vs IR (2)

IR don’t suffer from fluorescence problem
Raman microscopy produces higher spatial resolution image than IR. Fibre optics are common in Raman. IR and Raman are complementary techniques. (Case study - nifedipine, FTIR spectral changes as a function of time

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What is scattering?

When electromagnetic radiation (light) is incident on a system of particles it interacts with the particles and is scattered

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What is Rayleigh scattering?

When particle is much smaller than the wavelength. When a small particle absorbs a light photon, it immediately release a photon with the same energy (wavelength). The new photon is released in all direction. The small particle become a new point source o

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Describe features of diffraction (1)

If there are more than one particle adjacent to each other (in the order of the wavelength of the incident light), the scattered light will interfere each other. The interference is dependent on the angle of incident, wavelength and the spacing between th

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Describe features of diffraction (2)

A pattern of interference will emerge if a collimated monochromatic light was used, there are regular spacing between particles. Analysis of the interference pattern allows the determination of the spacing between the particles

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Describe features of diffraction (3)

X-ray is often used, because of the short wavelength (0.03-3nm), to probe intra and intermolecular spacing in crystalline materials (crystalline materials has regular molecular spacing)

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What is Bragg's Law?

nλ = 2d sin(θ). Constructive interference occurs when this condition is met

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State features of small-angle x-ray scattering

The X-ray beam is shone on the sample at angle θ. Diffracted X-ray beam is detected at angle 2θ. A signal is detected when the Bragg’s diffraction conditions are met. Data are generally collected at 2θ from 5 degrees to 70 degrees

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State features of powder diffraction: crystalline vs amorphous

Amorphous materials have no diffraction peaks.

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What are the stability issues?

Thermal dynamic stability issues. At high temperature (above Tg) or high relative humidity, which could plasticize the amorphous drug and lower the Tg, amorphous nifedipine is converted back to the more stable β form followed by the most stable α crystall

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What are the strategies to improve the stability of amorphous formulations?

Polymeric systems (limitation with polymer - hygroscopic, require large amount to be effective). Co-amorphous system. Opportunities with small molecules to form co-amorphous systems (less hygroscopic, tend to require less amount of excipient, IP space, QC

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Describe features of co-amorphous systems

Early formulations include the used of two drugs to create a co- amorphous system (limited choice). More recently amino acids are utilised to create co-amorphous systems. A range of amino acids are available. Some amino acids has high Tg.

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What are the challenges in the preparation of co-amorphous systems with amino acids? (1)

Spray drying, freeze drying require to co-dissolve both drugs and amino acids, which may be difficult to find if system does not form salt. May use water-organic solvent mixture as the solvent but need to consider freezing point (for freeze drying) and fi

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What are the challenges in the preparation of co-amorphous systems with amino acids? (2)

Ball milling is the most commonly used method for lab-scale manufacturing but it has its limitations

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What is the main problem with drugs?

Low oral bioavailability (caused by low solubility & dissolution rate)

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What are the common approaches used to improve dissolution rate?

Reduce particle size, add solubilising agents, formulate as a salt, formulate as a liquid, render drug into amorphous state (little knowledge about amorphous solid stability)

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State features of physical stability

Nearly all physical forms may interchange depending on processing or storage conditions. When preparing amorphous materials highly energetic or high-temperature methods are typically used e.g. milling/micronisation, spray drying or hot-melt extrusion

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What are the barriers to market for medicines containing a drug in its amorphous form?

Amorphous form low physical stability. Amorphous form low chemical stability. Will absorb water from the atmosphere. Expensive to produce. Difficult to process further

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What is spray drying?

Method used to produce dried product from aqueous solutions. Solution atomised (liquid converted to small droplets) and sprayed into stream of hot air. Results in free -flowing powder sample

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State features of the typical apparatus and methodology of spray drying

Apparatus: drying gas, drying chamber, atomiser, liquid feed, cyclone, exhaust gas, dry particles colelctor. Spray dried products recognized by hollow spherical shape, outer surface dried (entrapped water believed to blow hole in sphere to escape), partic

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What are the advantages of spray drying? (1)

Products dried very rapidly - each particle dried in less than 1 second, whole batch dried in seconds. Rapid and efficient drying results in low temperatures - heat input goes to evaporation rather than temperature increase. Investigated as a means of pre

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What are the advantages of spray drying? (2)

Product tends to be uniform size and free flowing, often with good compression properties. Spray dried products often used for tablet and capsule formulations, e.g. spray dried lactose, spray dried drugs such as paracetamol

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Describe the applications of spray drying (1)

Considerable interest in the use of spray drying as a means of preparing materials for dry powder inhalation due to good flow properties and well controlled size characteristics. E.g. spray dried salbutamol sulphate widely studied.

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Describe the applications of spray drying (2)

Also interest in spray drying as a means of preparing controlled release systems such as microspheres. Small spheres composed of drug and matrix which control the rate and/or site of delivery within the body, e.g. polylactic acid (PLA) microspheres.

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Describe the applications of spray drying (2)

Used for e.g. vaccine delivery to reduce frequency of application to single dose

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What are the disadvantages of spray drying?

Costs tend to be high and equipment can be bulky, e.g. 15m high by 6m diameter. Products are very often partially or completely amorphous (material with no long range order characterised by glass transition). This means material can recrystallise on stora

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What are the analytical methods used to determine the quality and stability of amorphous formulations prepared by spray-drying?

Glass transition temperature and weight fraction of water (acts as plasticizer). Evaluate use of PVP. Chemical stability (temperature, visible light, UV light). HPLC and LC-MS

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Describe features of freeze drying (1)

Liquid dilute in solution -> freezing -> sublimation primary drying -> evaporative secondary drying -> amorphous solid solution. Avoid thermal degradation.

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Describe features of freeze drying (2)

Water sublimes below its triple point: Typical parameters: Freezing -20°C, Annealing -80°C, Primary drying -40°C at a pressure of ≤ 0.01 mbar, Secondary drying ramp from -40°C to 25°C ≤ 0.01 mbar

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Describe features of freeze drying (3)

Assumes that a 1 to 10% w/v
aqueous solution may be prepared. Many drugs do not have the required aqueous solubility. Different solvents are required

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What are the requirements for a freeze drying solvent?

Relatively high freezing point -10°C to 30°C. Relatively high vapour pressure below freezing point e.g. >0.26mbar. E.g. water. Terbutanol - Freezing point = 24°C, Vapour pressure ≈ 36mbar at -20°C, Even better a potential solvent for class II BSC compound

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Is it possible to freeze dry in a capsule? (1)

Stable in ampoule but difficult to remove without affecting both physical & chemical stability. Solution -> freezing -> primary drying (-40 degrees Celsius, 0.076 mbar, 144h) -> secondary drying (25 degrees Celsius, over P2O5, 24h) -> freeze dried capsule

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Is it possible to freeze dry in a capsule? (2)

Different concentrations investigated - showed proof of concept via HPLC analysis, DSC, polarised microscopy, ATR FT-IR to monitor physical form/interactions

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Is it possible to freeze dry in a capsule? (3)

Only an amorphous formulation fully enhances dissolution. Chemically and physically stable over 3 months. Formulation development on mg scale for early clinical trial. Evidence of H bonding (NH and C=O) of stabilizing polymer to inhibit crystallisation)

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Amorphous Drug Formulations and Analysis

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