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212 test > preformulation studies > Flashcards

preformulation studies Flashcards

1
Q

Define preformulation studies

A

An investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage form

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2
Q

Why do compounds fail the discovery–> shelf process? (5)

A
  • Poor biopharmaceutical properties like squeous solubulity, stability, permeability, metabolism, oral bioavailability
    • Insufficient efficacy
    • Toxicity or side effects
    • Synthetic complexity and scale up (yields, crystalinity, impurities); too complex, too costly.
    • Changes in market place; techno-commerical decisions e.g. New emerging therapy will be invested into more.
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3
Q

What is significance of preformulation studies in drug studies? (5)

A
  • New chemical entity (NCE) should possess optimal biopharmaceutical properties to become a drug molecule
    • Potency and selectivity of NCE does not ensure drugability
    • Preformulation helps assess ‘drugability’ of a molecule
    • Tool to select and profile drug candidates and aid in formulation development based on scientific evdience
    • A necessary process to meet regulatory requirements
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4
Q

What is significance of preform studies in formulation development? (3)

A
  • Prior to dosage form development, fundamental physicochemical properties and derived properties of the drug are studied
    • Data dictates possible approaches of formulation development
    • Helps understand many subsequent events and mechanisms behind processes observed at latter stages.
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5
Q

What are fundamental properties to test for in preform studies and which of these are the minimum requirement? (8)

A
  • Analytical method
  • Solubility
  • Salts
  • Partition coefficient
  • Dissociation contant (pKa)
  • Melting points
  • Polymorphism
  • Stability studies

Solubility and pKa are required

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6
Q

What are derived factors to test for in prefrom studies? (5)

A
  • Microscopy
  • Particle size
  • Bulk density
  • Flow properties
  • Excipient compatibility
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7
Q

Describe parameters for solubility of the NCE

A
  • Aqueous solubility should be greater than 1% (10mg/mL) over the pH range 1-7 at 37 degrees C.
    • Solubility of less than 1mg/mL indicates the need for a salt, especially if the drug is formulated in a solid dosage form where dissolution of the drug is important
    • Dissolution rate of drug should be greater than 1mg/cm/cm/min if the dissolution rate is less than 0.1mg/cm/cm/min, then it will likely give dissolution rate-limited absorption.
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8
Q

What is intrinsic solubility and how should this be measured?

A

Intrinsic solubility is the solubility of a drug in an unionised form.
If the drug is a weak acid, its solubility should be measures in a strong acid and the same for bases.

Solubility should be measures at 4 degrees as these are likely storage conditions, and at 37 degrees as this is body temp.

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9
Q

Describe how the dissociation constant is relevant to solubility and how this can be applied.

A

pKa is relevant to ionisable drugs, and allows the informed use of pH to maintain solubility and selection of salts to achieve good F and improved solubility.

Henderson-hasselbalch equation can be used to determine pKa by changes in solubility and to predict solubility at any pH provided intrinsic solubility and pKa are known.

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10
Q

How do salts effect NCEs and how is this applied?

A

Salts are the chemical combination of two ionisable components. If the pKa of an acid and base are too close, stable salt will not form.

Accpetable salt counter ions are:

  • basic (anions): HCL, sulfate, citrate etc
  • acidic (cations): potassium, sodium, calcium etc.

Salts prepared from strong acids or bases are freely soluble and very hygroscopic, causing drugs to degrade faster.

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11
Q

What is the partition coefficient and how is thsi found?

A

This tells us how compounds will partition between an oil and aqeuous phase.

  • log P > 1 = lipophilic
  • log P < 1 = hydrophilic

This is determined by the shake flask method, where how the drug partitions into either phase is indivative of log P and associated properties.

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12
Q

How can melting point be determined and what relevance does this have to a NCE?

A

MP provides info regarding thermal properties of materials and drugs. The potental stability of a NCE can be predicted from this.

MP can be found by;

  • capillary melting
  • DSC
  • hot stage microscopy
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13
Q

What are polymorphisms and what does this tell us about compounds?

A

Polymorphisms are different crystalline structures of chemically same compounds. These will have different properties due to their structure.
Compounds tend to crystallize into their most stable form, where MP is also the highest. This then indicates info about solubility - where this is related by latent heat of fusion.
Metastable forms are other forms of polymorphs, however these tend to convert into the most stable form - but this may have better solubility.

Knowledge of polymorphs can be considered when formulating a NCE, and can be determines using optical mciroscopy and DSC.

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14
Q

How is drug and product stability tested?

A

Stability is tested fro my putting the NCE under stress conditions. This can be high heats, moisture exposure, pH conditions, light, oxidation and physical stress.

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15
Q

How can derived properties of NCEs be tested for?

A

Basic crystallography to determine;

  • crystal morphology
  • polymorphism
  • solvates

Particle size analysis

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16
Q

What does particle size influence? How can it be determined?

A

Particle size influences:

  • dissolution rate
  • suspendibility
  • uniform distribution
  • penetrability
  • lack of grittiness

Particle size can be determined by:

  • sieving
  • optical microscopy
  • sedimentation
  • coulter counter
  • laser diffraction
17
Q

Why is excipient compatibility important? How can excipient compatibility be determined and how is this observed? What factors are considered?

A

Excipient compatibility involves the careful selection of excipients for formulation of stable and effective dosage forms

  • excipients facilitate administration
  • promotes consistent release and F
  • protects active ingredients from degradation
Determination by; DSC.
A 50:50 drug:excipient mixture is prepared and examined under nitogren at standard heating rate.
Changes seen on grpah reading indicates interaction of drug with excipients, where observable aspects can be;
- glass transition
- crystallization
- melting
- cross-linking
- oxidation

212 test (17 decks)

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