Pharmaceutical solids

PHAR2000

• to turn a raw drug chemical into a safe, effective, and easy-to-use medicine to achieve its therapeutic outcome

purpose of dosage form design

• Therapeutic considerations

• Biopharmaceutical factors

• Patient compliance and convenience

• Safety and stability

• Manufacturing considerations

key considerations in dosage form design

• physical nature of the selected drug candidate needs to be decided during the preclinical phase of drug development

• Solids are held together by two types of binding forces – intermolecular and intramolecular

• Properties of solids, such as the structure of solids (amorphous vs. crystalline), melting point, and solubility are influenced by the binding forces

• stronger intermolecular force, higher melting point, lower solubility

solid forms of drug

• The rate of absorption of many slightly soluble drugs from the gastrointestinal tract and other sites is limited by the rate of dissolution of the drug

absorption of a drug (bioavaliablity)

• Physical form (crystals vs amorphous)

• Solid-state characterisation (e.g., polymorphism screening)

• Salt selection

what effects drug solubility

• have an ordered form

• arranged systematically within the solid, forming a symmetric repeating pattern

• A single unit cell or building block is organised in three dimensions to construct the crystal.

• arranged at regular intervals in each direction, and extend indefinitely and homogeneously throughout the crystal.

• Very stable systems with distinct physical properties, such as melting points

• contains basic unit cells for all possible crystals

crystalline solids

• no ordering pattern in structure

• isotropic meaning they exhibit similar physical properties in all directions

amorphous solids

• Similar squares could be drawn on all the sides to form a cubic repeating unit,

• Each unit cell is the same size and contains the same number of molecules or ions arranged in the same way.

• seven possible primitive unit cells with atoms or molecules only at each corner of the unit cell.

unit cell crystal structure

• manifests itself as a sudden excruciating pain in the big toe (usually of men), although other joints such as the ankle, heel, instep, knee, wrist, elbow, fingers or spine may be affected

• precipitation of needle-like crystals of uric acid

• form of monosodium urate, on the articular cartilage of joints when the levels of uric acid in blood serum

gout crystallisation

• Supersaturation (alot of the drug) of the solution

• super saturated molecules attach to the nuclei causing the formation of crystal nuclei

• Crystal growth round the nuclei

crystallisation proccess

• solution or vapor holds more dissolved solute or substance than is normally possible at a given temperature,

supersaturation

• changing the pH to induce precipi tation

• Done instead of using a nuclei

• cause the drug to precipitate out, become the nuclei for precipitation

• made to occur from a homogeneous solution by slowly generating the precipitating agent by means of a chemical reaction.

• Precipitation by direct mixing of two reacting solutions sometimes does not bring about immediate nucleation and, as a result, the mixing stage may be followed by an appreciable lag time

• precipitation - more of a chemical reaction, while crystal nuclei is a phase change

how crystal nuclei is different to precipitation

• insufficient to cause crystals to form by itself

• the crystal embryos must form by the collision of solute molecules in the solution,

• the addition of seed crystals, dust particles, or even particles from container walls.

• Deliberate seeding - dropping nuclei into the solution to form crystals

• seed crystals do not necessarily have to be of the substance concerned but may be isomorphous substances

formation of crystal nuclei

• As soon as stable nuclei are formed, they begin to grow into visible crystals.

• in the growth, transport of the molecules to the surface and their arrangement in an ordered fashion in the lattice.

• deposited continuously on a crystal face at a rate proportional to the difference of concentration between the surface and the bulk solution

• crystals generally dissolve faster than they grow, so growth is not simply the reverse of dissolution.

crystal growth

• to create different habits ( structural formations), the conditions need to be changed

• These crystal habits usually have the same internal structure, and so have the same X-ray diffraction patterns.

• The rate of precipitation is an important factor in determining habit, involving nucleation and subsequent crystal growth.

• Effect of solvents on habit: Generally, less-viscous media favour the growth of coarse and more equidimensional crystal forms

crystallisation conditions affect habits

• crystal habit can be modified by adding impurities (called poisons) to the solvent used for crystallisation, which changes the structure

• surfactants in the solvent medium used for crystal growth (or, for example, in stabilisation or wetting of suspensions) can alter crystal form by adsorbing onto growing faces during crystal growth.

Crystal habit modification

• each substance may have different crystal habits (apperance)

• this includes the faces, number and kind of faces

• goes from tabular to prismatic and acicular, all have the same internal structure but different physical properties

formation of crystals

• When the molecules arranged internally in two or more different ways in the crystal;

• may be packed differently in the crystal lattice

• differences in the orientation or conformation of the molecules at the lattice sites, polymorphism occurs.

• variations cause differences in the X-ray diffraction patterns of the polymorphs and this technique is one of the main methods of detecting the existence of polymorphs.

• Different inter- and intramolecular interactions such as van der Waals interactions and hydrogen bonds will be present in different crystal structures (polymorphs)

• Different polymorphs will have different free energies and therefore different physical and chemical properties such as solubility, chemical stability, melting point, density, etc., and they also usually exist in different habits.

polymorphism

• produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to 0°C. Melting point 205°C.

Spironolactone needle form

• roduced when the powder is dissolved in acetone, dioxane or chloroform at room temperature and the solvent is allowed to evaporate spontaneously over a period of several weeks.

spironolactone prisms form

• readily produced by crystallisation from aqueous solution and many other solvents; is the more thermodynamically stable at room temperature and is the commercially used form. Not suitable for direct compression into tablets and has to be mixed with binding agents before tableting.

paracetamol monoclinic form

• forms elongated prisms.

• difficult to isolate through standard cooling. It usually requires heterogeneous nucleation, where the solution is "seeded" with existing Form II crystals to guide the molecular arrangement.

• form exhibits superior plastic deformation. When the tablet press applies force, the crystal layers slide over one another rather than snapping.

• high compressibility makes it a candidate for direct compression (making tablets without extra binders or wet granulation), which can significantly lower manufacturing costs and complexity.

• more preferred

paracetamol orthorhombic form

• determine which of the two polymorphs is the more stable

• polymorphs are placed in a drop of saturated solution (is needed) under the microscope.

• crystals of the less-stable(meta-stable)form will dissolve and those of the more stable form will grow until only this form remains.

• less stable form can reorganise its structure to become more stable

• drugs with more than two polymorphs we need to carry out this experiment on successive pairs of the polymorphs of the drug until we eventually arrive at their rank order of stability.

determining stable crystal form

• different polymorphs arise through different arrangements of the molecules or ions in the lattice, they will have different interaction energies in the solid state.

• the polymorphic form with the lowest free energy will be the most stable, and other polymorphs will tend to transform into it.

• release of energy, makes it more stable

• rate of conversion is variable and is determined by the magnitude of the energy barrier between the two polymorphs – the higher the energy barrier and the lower the storage temperature, the slower is the conversion rate.

crystal polymorph transformation

• transformation between polymorphic forms can lead to formulation problems.

• Phase transformations can cause changes in crystal size in suspensions and their eventual caking.

• Crystal growth in creams as a result of phase transformation can cause the cream to become gritty.

• Similarly, changes in polymorphic forms of vehicles, such as theobroma oil used to make suppositories, could cause products with different and unacceptable melting characteristics.

• vital that sufficient care is taken to determine polymorphic tendencies of poorly soluble drugs.

• designed to release drugs at the correct rate and so that intelligent guesses can be made before clinical trials about possible influences of food and concomitant therapy on drug absorption.

pharmaceutical implications of polymorphism

• the most stable polymorph often has a lower bioavailability than the metastable polymorph

• most stable polymorph usually has the lowest solubility and slowest dissolution rate and consequently often a lower bioavailability than the metastable polymorph.

• more stable - less solubility and less bioavailability

bioavailability

• free energy differences between the polymorphs are small there may be no significant differences in their biopharmaceutical behaviour as measured by the blood levels they achieve

• Only when the differences are large may they affect the extent of absorption.

• Particle size reduction may lead to fundamental changes in the properties of the solid. - increase bioavaliability

• Grinding of crystalline substances such as digoxin can lead to the formation of amorphous material with an intrinsically higher rate of solution and therefore apparently greater activity - increase bioavailability

• importance of the polymorphic form of poorly soluble drugs that must be controlled.

bioavailability difference of polymorphs

• Predictability of the phenomenon is difficult except by reference to past experience.

• The pharmaceutical importance of polymorphism depends very much on the stability and solubility of the forms concerned.

• It is difficult, therefore, to generalise, except to say that where polymorphs of insoluble compounds occur, there are likely to be biopharmaceutical implications.

Pharmaceutical importance of polymorphism

• drugs needs to be present in the body, which is done by different routes of administration

• be absorbed - bioavailability for therapeutic effect

understanding of drugs

• new chemical entity discovered

• pre-clinical studies - dosage form, manufacturing and compounding

• investigating drug application

• trials

• new drug application

drug discovery

• using X ray diffraction

• crystalline - large peaks

how to determine the difference between crystalline and amorphous structure

• dissolution of drug - surface area to volume ration

• injectability - whether it can be injected

• tabletting - ease compression and flow properties

physical properties that change based on crystal habits ( crystal structure

• more than one component in the crystal structure

• comes from the crystallisation process itself

• if it has a water component - hydrate

• solvent component - solvate

• no solvent component - pure

• no water component - anhydrates

multi component crystals

crystal forms of the same substance that incorporate solvent or water molecules (solvates/hydrates) into their lattice structure,

pseudopolymorphs

• solvent plays a role in holding crystal together

• hydrogen bonding in network

• stable and hard to desolvate

• collapse when solvent is lost and recrystallise in a new crystal form

polymorphic solvates

• merely occupies voids in the crystal

• desolvation doesnt destroy crystal part of lattice

• solvent molecules within the crystalline structure

• that separates from a liquid solution or loses its associated solvent molecules easily,

pseudopolymorphic solvate

• hydrates, anhydrous and solvates all have different melting points and solubilities

• anhydrous forms show similar higher solubilities than hydrated materials - more interaction with water as it lacks it in its structure

• hydrate interacted with water, energy released for crystal break up on interaction of the hydrate with solvent is less than anhydrous

• hydrate, anhydrates, solvates - increasing solubility

• solvates require less energy to be dissolved

solubility of crystals

• combination of crystals with something else to increase water solubility

• crystal composed of drug and crystalline solid

• if doesn’t produce good solubility it can be converted into a salt - weak acid or base

• alter the physical properties

• lower hygroscopicity and higher solubility

• metastable (temporarily stable) - change crystal properties

co-crystal

• they will have different solubility, stability and dissolution and compression characterisitics to normal crystals

• higher solubility than crystals

• higher energy state, thus unstable, increase in molecular mobility, causes rearranging of structure into crystal

• higher degradation and stronger chemical reactivity due to mobility, difficult to maintable compound in amorphous state

• high bioavaliability

amorphous solids convert into crystalline form

• accelerate the proccess of crystallisation into a 3d lattice

• crystalline to amorphous uses mechanical or thermal energy

• some substances cant be converted into crystals but can be converted into semi-crystallin

production of amorphous solids

• dont have sharp melting points

• but change in the properties of the material known as glass transition temperature

• in high tg the molecules become more mobile and degradation increases

• used to determine the different amorphous or sem-crystal materials

amorphous or semi-crystalline materials

• thermal techniques - differential scanning calorimetry (dsc)

• in the glass transition appears as a endothermic heat capacity reflected in a baseline step

• tg can vary in sharpness and extend over a temperature

determining tg

• decide whether it is more desirable to develop the uncharged molecule

• salt is only used if clear advantages, used if their is low solubility, not crystallisable, low melting point, low chemical stability, high hygroscopicity

salt selection