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828 Dosage > Lecture 3: Formulation and API > Flashcards

Lecture 3: Formulation and API Flashcards

1
Q

Drug product performance

A

-ability of drug to elicit therapeutic response and stay in a safe range during dosage
-no toxic response
-described by pharmacokinetics and parmacodynamic processes

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2
Q

Goal of Formulations

A

-transfer a new therapeutic compound
-develop reproducible dosage form

-release from dosage form must balance the way body processes medicine

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3
Q

reproducible

A

-refers to each dosage form containing same amount of drug
-refers to same performance in the body

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4
Q

Drug blood level vs time graph

A
  1. Absorption: increase up to Cmax, Tmax (2hoursish)
  2. slow decrease through distribution, metabolism, excretion
    AUC= area under the curve
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5
Q

Disposition phase of drug

A

distribution, metabolism, excretion

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6
Q

Elimination phase of drug

A

metabolism and excretion

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7
Q

Dosage form controls

A

-absorption, dissolution, degradation in intestinal tract

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8
Q

Body controls

A

metabolism, distribution, excretion

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9
Q

Drug upon Administration

A

Intestinal tract (dosage form controls) –> portal vein –> liver (metabolism) –> blood –> peripheral tissues (distribution), perfused tissue, and urine (excretion)

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10
Q

Absorption rate

A

-MUST BALANCE DISPOSITION
-begins declining as disposition starts to increase
-Kabs

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11
Q

Kabs defined by

A

-drug properties
-excipient/composition of formulation
-physiological barriers between GI tract and systemic circulation

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12
Q

Margin of Safety

A

-goal of dosage form design
-area between pharma and toxicology

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13
Q

Drug discovery: Assessing translation

A

-finding chemistries that can mitigate disease
-driven by receptor binding
-druggability and developability

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14
Q

Druggability

A

-binding and “drug-like” properties favorable for product translation

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15
Q

Developability

A

assessment to characterize if new molecules can be formulated

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16
Q

Druggability stages

A
  1. discovery
  2. Assess ability to bind to drug target
  3. in vivo models used to assess
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17
Q

Developability stages

A
  1. refers drug performance
  2. incorporates factors like solubility/dissolution
  3. incorporates formulation factors related to ADME/T
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18
Q

Druggable genome

A

-genes that encode disease related proteins that can be modded by drugs
-includes differentially regulated drugs
-vary in intensity upon comparative analysis

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19
Q

Healthy vs sick gene expression

A

-this contrast can yield genes that may serve as targets for drug design

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20
Q

Druggable targets

A

mostly disease genes

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21
Q

Druggable gene identification

A

via pharmacogenomic methods

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22
Q

Druggable proteins

A

-proteins that can bind drug-like compounds with affinity < 10mM
-compound must be able to modulate the protein

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23
Q

Druggable proteins identification

A

-via genes of disease-related proteins that be modulated by drugs

24
Q

Druggable pharmacophore

A

-druggable genes converted to proteins via in silico methods

25
Q

Druggable pharmacophore identification

A

binding cavities

26
Q

Pharmaceutically tractable genome

A

-genes that encode proteins that can be targeted by smaller compounds, antibodies, and therapeutic proteins for pharmaceutical use

27
Q

Drug candidate to tractable gene + protein associated with disease

A

= mitigated disease yay

28
Q

Pharmacophore drug design

A

-proteins associated with disease modeled to find binding pockets
-drugs fitting these pockets generated
-chemicals can be made to optimize drug binding

29
Q

Pharmacophore drug design applications

A

-virtual screening
-de novo design

30
Q

New chemical entities (NCE)

A

-generated to fit a pharmacophore
-characterization to assess drugability

31
Q

Good druggable entities

A

-do not equal a good potential to be translated

32
Q

ADMET

A

T is toxicity

33
Q

Developability

A

-centers on evaluating properties that will be used to generate a working formulation

34
Q

Pharmacokinetics and pharmacodynamics

A

-main indicators of safe and efficacious use
-do NOT vary across patient populations

35
Q

Goal of Drug Delivery

A

Drug + vehicle
-vehicle has selected properties to overcome barriers and transport it from administration site

36
Q

Formulation design considerations (performance factors)

A

-physicochemical properties of the drug
-properties and composition of formulation
-biological factors (ADMET)
-MUST be properly balanced

37
Q

Performance

A

-drug response and therapeutic range
-lack toxicity
-function of the drug

38
Q

Physicochemical Properties of the Drug
that Affects Absorption

A

-solubility
-drug stability in solution
-lipophilicity
-molecular size/shape
-pKa of groups
-physical state of drug

-SLIDE 31

39
Q

Solubility depends on

A

-molecular structure
-physical state
-composition of solvents
-measurement methods

40
Q

solid physical state

A

amorphous, crystalline, polymorphic

41
Q

liquid physical state

A

predissolved in solvent

42
Q

Composition of solvents

A

-types
-cosolvent %s
-solution components (salts, ions, lipids, ets)
-pH and temp

43
Q

Measurement Methods

A

-equilibration time
-detection method

44
Q

Partition Coefficient

A

-ratio of concentrations in two immiscible solvents (octanol and water)
-Ko/w = Coct / Cwater

45
Q

pH-partition hypothesis

A

-permeability transport depends on the fraction of unionized drug at intestinal pH
-for drugs absorbed by passive, transcellular mechanism

46
Q

solubility and partition coefficient

A

-as Ko/w increases, solubility decreases
-formula SLIDE 34

47
Q

pH and pKa

A

-important in determining absorption of weak acids vs weak bases

48
Q

Cell membrane structure

A

-lipid bilayer with lipid and protein molecules

49
Q

protein to lipid ratio in the GI tract

A

1:7 ??
-octanol:water partitioning not accurate predictor of physiological conditions

50
Q

Organelle pH

A

-differences in extracellular and intracellular values affect transport
-can trap molecule in a cell

51
Q

Overcome effects of pH partition hypothesis

A

-functionalize the compound-change pKa
-prodrug strategy
-salt selection
-drug delivery system

52
Q

prodrug strategy

A

-modifiy charged moiety
-modify molecule to be recognized by transporter

53
Q

Salt selection

A

-ion pairing effective in improving permeation
-form can alter unionized fraction

54
Q

Polar Surface Area (PSA)

A

-solvent accessible surface area (SASA) provided by O, N, H
-good estimate of H bond potential
-does NOT account for charges

55
Q

Poor absorption/permeation when:

A

-more than 5 H bond donors
-more than 10 H bond acceptors
-MW over 500
-MlogP over 4.15 (ClogP over 5)

828 Dosage (27 decks)

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