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Ceutics2 - Midterm 1 > 7 - Solids Theory > Flashcards

7 - Solids Theory Flashcards

1
Q

Tablets vs Capsules

in terms of economy/production

A

Tablets take EXTRA TIME & WORK to develop

almost Never used in early clinical studies

CHEAPER to MASS PRODUCE

Ultimately we want a capsule dosage form that can be EASILY converted to a tablet

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2
Q

Tablets vs CAPSULES

in terms of market/economy

A

MORE COSTLY to MASS PRODUCE

almost NEVER favored for marketed products to have HIGH sales volume, unless tablets are TOO difficult to make

Ultimately we want a capsule dosage form that can be EASILY CONVERTED to a tablet

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3
Q

Hard Shell Capsule

Extemporaneous Compounding

A

Relatively Easy to formulate & Dispense for low-volume dispensing

Ex. custom dose strengths for INDIVIDUAL patients

Preferred for first-in-man clinical studies due to EASE in:

dispensing / control over distribution

simplicity for dose adjustment

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4
Q

Basic PhysicoChemical Properties

for designing a Formulation

A

S + S + SS

Chemical Stability

Temp / pH / oxidation / photochemistry

Solubility

pH / lipophilicity

Solid State Properties of the API

crystal form / salt form (if API is ionizable)

physical stability

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5
Q

Stability

Tablet & Capsule Dosage Forms

A

drug must be CHEMICALLY STABLE

Pass through GI tract in solution

survive manufacturing conditions

pH effects

(pH 1-2 / 6-8 / 11-13)

last for several years in solid state

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6
Q

Soluble

Tablet & Capsule Dosage Forms

A

drug must be Adequately SOLUBLE

Some solubility in water & lipids

in order to be bioavailable by absorption through GI tract walls

OR

target for a TRANSPORTER SYSTEM

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7
Q

Solid State

Tablet & Capsule Dosage Forms

A

Drug must have Desireable SOLID STATE properties

thermodynamically most stable crystalline polymorphic form is desired, adequate solubility

if solubility is INadequate, it can be enhanced, if drug can be produced in a:

metastable crystalline polymorphic form or as the amorphous form

as long as these forms can be PREVENTED from converting to more stable/less-soluble forms

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8
Q

What is the MOST PREFERRED Solid State form?

A

thermodynamicaly most stable

Crystalline Polymorphic Form

if this form has adequate solubility!

Amorphous / Metastable crystalline form will suffice if the solubility is inadequate

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9
Q

Evaluation of Chemical Stability

STABILITY - Tablet & Capsule Formulation

A

using stress degradation experiments that determine the effect of:

HEAT + HUMIDITY

RXN w/ SOLVENTS (and effect of pH in aqueous solutions)

RXn w/ OXIDIZING AGENTS

Sensitivity to UV & VISIBLE LIGHT

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10
Q

Thermal Degradation

STABILITY - Tablet & Capsule Formulation

A

only an acceptable small degradation, when heated to

90*C** in solution for **ONE WEEK

sufficient enough for a liquid product for oral/parenteral use

Also test degradation at:

pH of 1-2 / 6-8 / 11-13

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11
Q

Thermal Degradation - pH levels

STABILITY - Tablet & Capsule Formulation

A

ph 1-2 for Stomach Acid

ph 6-8 for Intestinal Fluid

pH 11-13 for Cleaning Media

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12
Q

Solvolysis

STABILITY - Tablet & Capsule Formulation

A

Test for Reactions in the Solution, Buffers

Degradation in aqueous media over a range of pH values may permit ID of a

specific pH for MAXIMUM Stability

choice of solid state form for ionizable substances - salt maybe more stable

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13
Q

Oxidation

STABILITY - Tablet & Capsule Formulation

A

Reaction with different types of commonly encountered Oxidizing agents like:

Peroxides

Heavy metal ions +/- Oxygen

Radical initiators +/- Oxygen

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14
Q

Photolysis

STABILITY - Tablet & Capsule Formulation

A

Rxn when exposed to electromagnetic radiation

UV + Visible Light

UV mimics effect of exposure to ionizing radiation

packaging important

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15
Q

4 Effects to stress test for SOLUBILITY

STABILITY - Tablet & Capsule Formulation

A

TSOP

Thermal Degradation

Solvolysis

Oxidation

Photolysis

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16
Q

Evaluation of Solubility

SOLUBILITY - Tablet & Capsule Formulation

A

Ionization

Lipophylicity

Intrinsic Dissolution Rate

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17
Q

Ionization & Stability

SOLUBILITY - Tablet & Capsule Formulation

A

Many drugs contain chemical moieties (A/B or FxnGroups) that can ionize in AQSolution

Solubility of ionized forms is MANY FOLDS HIGHER in water

pH solubility profile should be generated

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18
Q

Lipophilicity

SOLUBILITY - Tablet & Capsule Formulation

A

Optimal obsorption of uncharged drug substances occurs if the drug has about a

100x higher LIPID solubility vs water

but the water solubility must be ENOUGH to dissolve the entire dose in 250-500mL of aqmedia

pH between 1-7

19
Q

Intrinsic Dissolution Rate

SOLUBILITY - Tablet & Capsule Formulation

A

Rate at which a compacted disc of this solid dissolved in media = GI Fluids (in stomach/intestines)

Should be measured

20
Q

Solid State form Selection -

Polymorph Screening

Solid State form Selection - Tablet & Capsule Formulation

A

Crystalline or Amorphous

Salt or Solvate

21
Q

Crystal Polymorphism

Solid State form Selection - Tablet & Capsule Formulation

A

many drugs, esp those with higher MW & limited structural mobility, tend to

Crytallize in MORE THAN 1 polymorphic form

can lose all short-range structure and become amorphous

22
Q

Physical Properties of Crystal Polymorphs

Solid State form Selection - Tablet & Capsule Formulation

A

thermodynamically MOST stable Polymorph has:

HIGHEST Melting Point (good)

  • lowest Solubility (bad)*
  • slowest Intrinsic Dissolution rate (ugly)*
23
Q

Solvates & Co-Crystals

Solid State form Selection - Tablet & Capsule Formulation

A

Some substances crystallize with added solvent molecules trapped in the crystal lattice

Solvation may either STABILIZE or DE-Stabilize reactivity of the solid toward external solvent vapor

Also, other dissolved substances may co-crystillize with the drug to produce a new crystal lattice w/ altered phys properties + altered solid state chemical stability

24
Q

Amorphous Solids

Solid State form Selection - Tablet & Capsule Formulation

A

fewer short-range entropy-restricting structural constraints

Physically unstable: spontaneously crystallize

Typically more soluble + faster intrinsic dissolution rate

Typically less chemically stable - more like a drug in solution

Only plus is the solubility / dissolution, no actual formulations that are amorphous YET

25
Q

Preformulation Studies

Issues with S,S,& SS

A

May LIMIT Dosage form choices

May Dictate constraints on manufacturing processes

may Impact costs of development

analog w/ better S+S+SS properties may be better drug candidaete, even if it is not as potent

26
Q

Identity & Purity of API

A

Active Pharmaceutical Ingredient

Imupurities within acceptable limits

Drug myst actually be what it purports to be

27
Q

Only a few drugs are formulated without adding some excipients to make manufacturing possible:

A

Filler

Disintegrants

Binders

Lubricants / Anti-Adherants

Glidants

Capsule Shell

Color / Flavor / Coating

28
Q

Other Excipient Design additions

A

Verify IDENTITY & QUALITY

Prevent CONTERFEITS

Moisture content / Impurities

29
Q

Excipients required to make drug products manufacturable are inert ingredients?

True or False and why

A

FALSE

Excipients are NOT inert ingredients

They can have incompatabilities that affect the drug by:

Stability

Solubility

Solid State Properties

30
Q

Excipients -

Test for Trial formulations or Binary Combinations?

A

TRIAL FORMULATIONS

use the best of several candidate trial formulations

In the past we prepared binary mixtures THEN examined for S,S,SS properties

COMBINATIONS of exipients exert MULTIPLICATIVE and not just additive effects on S,S,SS properties

31
Q

Bulk Properties

A

All must be determined BEFORE manufacturing procedure:

Particle size may also require modification

Particle size Distribution

Bulk + Tap Density

Angle of Repose

Flow Properties

32
Q

Preferred Dose / Size of solid dosage form

A
  • Impractical to deliver LARGE DOSES >1gram*
  • Also impractical to deliver Small Doses <10mg*

without the use of extensive dilution using fillers

likely to have mixing/content uniformity problems

33
Q

When is Bioavailability tested for in clinical trials?

A

PHASE 1

It is critical to establish that the drug is actually released from the dosage form & absorbed into the body

“Phase Zero” initial estimates of PK & PD properties

34
Q

IVIVC

A

Attemp is made to devise dissolution test conditions

In Vitro that Correlate with In Vivo

Product dissolution studies are conducted to measure drug release from the dosage form under laboratory conditions;

35
Q

What is observed in DISSOLUTION TESTING?

A

Tablet must first disintegrate / Capsule must first break open

then dispersed & dissolved

This process must occur CONSISTANTLY with minimum variation in performance

with multiple samples of he dosage form

36
Q

How is dissolution testing done?

A

done using Aqueous Media

pH 1-2 to mimic stomach acid

pH 5-7 to mimic intestinal fluid

Sometimes surfactants & enzymes are added to mimic bile surfactants & pancreatic enzymes

900mL test volume @ 37*C + Controlled vessel geometry + controlled stirring rate

37
Q

At what phase do the studies indicate that controlling BV may lead to BETTER EFFICACY when compared to adverse drug effects?

A

PHASE 2

It is normally prudent to develop an IR dosage form for

FIRST-IN-HUMAN Studies

Phase 1 dosage form can be re-designed & re-engineered to modify the drug release rate (slow it down) so it can achieve a longer duration of action

and/or

steadier plasma conc

38
Q

Packaging

in terms of Drug Formulation

A

Drug must be dispensed in some sort of container

Bottles / Vials = Glass / Plastic

+ Caps / Cap liner / anti-tampering seal

Blister Packs = plastic film laminate, foil laminate

Compatibility of the packaging must be evaluated:

Moisture / Light Barrier?

any Sorption of drug to components of packaging?

39
Q

Storage

​in terms of Drug Formulation

A

Changes in S,S&SS must be evaluated throughout the planned shelf life of the drug under anticipated storage conditions

Product must PERFORM “Essentially Indetically” at the end of the shelflife.

Equal to how it worked when it was FIRST manufactured

40
Q

Quality Assurance

​in terms of Drug Formulation

Multiple specifications must be met with on-targ results having minimum variation

Accuracy & Precision are both important

A
  • API meets all specs
  • Dissolution adequate
  • Weight within correct range
  • CORRECT Potency
  • Moisture content within limits
  • Acceptable Appearance
  • Degradation products within limits
  • Mechanical properties acceptable
  • Free from microbial contamination
  • Contents sufficiently uniform
  • Size & Shape within design specs
41
Q
A

Clinical Development Map

42
Q
A

API Development Map

43
Q
A

Dosage form Development MAP

Ceutics2 - Midterm 1 (7 decks)

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