Factors Affecting Drug Absorption

PHYSICOCHEMICAL FACTORS
AFFECTING DRUG ABSORPTION
Ver 15.0
2022.5.11
작성자 : 임창백

1) Drug solubility & dissolution rate
2) Particle Size and Effective Surface Area of the Drug
3) Polymorphism and Amorphism
4) Hydrates/Solvates (Pseudo polymorphism)
5) Salt form of the drug
6) Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis
7) pKa of drug & gastrointestinal pH hypothesis
8) Drug stability
Physicochemical Factors Affecting Drug Absorption
2

Consider the events that occur following oral administration of a solid dosage form.
Except in case of controlled-release formulations, disintegration and
deaggregation occur rapidly if it is a well-formulated dosage form.
☞ The two critical slower rate-determining processes in the absorption of orally
administered drugs are:
 Rate of dissolution
 Rate of drug permeation through the biomembrane.
 Dissolution is the RDS for hydrophobic, poorly aqueous soluble drugs like griseofulvin
and spironolactone; absorption of such drugs is often said to be dissolution rate-limited.
 If the drug is hydrophilic with high aqueous solubility—for example, cromolyn sodium or
neomycin, then dissolution is rapid and RDS in the absorption of such drugs is rate of
permeation through the biomembrane.
 In other words, absorption of such drugs is said to be permeation rate-limited or
transmembrane rate-limited
1. Drug Solubility and Dissolution Rate
3

The two rate-determining steps in the absorption of drugs from orally
administered formulations
4

 Based on the intestinal permeability and solubility of drugs,
Amidon developed Biopharmaceutics Classification System (BCS) which classifies the
drugs into one of the 4 groups
 Class I drugs (high solubility/high permeability) are well absorbed orally since they have
neither solubility nor permeability limitation.
 Class II drugs (low solubility/high permeability) show variable absorption owing to
solubility limitation.
 Class III drugs (high solubility/low permeability) also show variable absorption owing to
permeability limitation.
 Class IV drugs (low solubility/low permeability) are poorly absorbed orally owing to
both solubility and permeability limitation
6

 An important prerequisite for the absorption of a drug by all mechanisms except
endocytosis is that it must be present in aqueous solution.
 This in turn depends on the drug’s aqueous solubility and its dissolution rate.
 Absolute or intrinsic solubility is defined as the maximum amount of solute dissolved
in a given solvent under standard conditions of temperature, pressure and pH.
 Dissolution rate is defined as the amount of solid substance that goes into solution per
unit time under standard conditions of temperature, pH and solvent composition and
constant solid surface area.
7

Key factor
first-pass effect
absorption metabolism
excretion
distribution

9

10

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 Class boundary parameters (solubility, permeability, and dissolution) are for easy
identification and determination of BCS class
 Solubility
 A drug substance is considered highly soluble when the highest dose strength is
soluble in 250 mL or less of water over a pH range of 1–7.5 at 37 °C
 Permeability
 A drug substance is considered highly permeable when the extent of absorption in
humans is greater than 90% of an administered dose, based on mass-balance or
compared with an intravenous reference dose
 Dissolution
 A drug product is considered rapidly dissolving when 85% or more of the labeled
amount of drug substance dissolves within 30 min using USPApparatus 1 or 2 in
a volume of 900 mL or less of buffer solutions
BCS CLASS BOUNDARIES

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Measurement of permeability
 신약후보물질로부터 신의약품 개발을 위해 효과적인 스크리닝 방법을 확립하기 위한
연구가 활발히 진행
 선진국의 경우 효율적인 in vitro 체내대사 고속 평가 방법의 개발로 단시간 내 에 많
은 후보물질들의 체내대사를 효과적으로 검색 가능한 방법을 사용
 방법의 하나 로 초기 연구단계에서 장관 투과성 평가를 위해 세포주를 이용한 실험
방법이 사용
 경구투여한 약물의 장내 투과성 평가를 in vivo 실험을 통해 확인하려면 많은 시간과
비용이 소요되는데 반해 세포주를 이용한 방법은 장관 상피세포와
유사한 세포주를 membrane filter에 배양한 실험방법을 이용하여 투과도를
측정할 수 있는 방법
 투과성 실험계의 확립을 위한 Caco-2와 MDCK 세포를 비교 연구
 소장 상피 세포주를 이용한 투과성 예측
 용해도에 따라 4가지 그룹으로 나누는 BCS 에서는 소화관 투과성 측정
☞ Caco-2 세포의 사용이 보다 정확하게 분류됨
☞ Caco-2 세포의 활용이 투과성 시험에 용이

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 transwell의 membrane을 사이에 두고 두 개의 배양액 중 상층의 배양액에 Caco-2 세
포를 3주 정도 배양시켜 cell layer에 의해 발생하게 되는 전기저항치(TEER: trans-
epithelial electrical resistance)측정을 통해 안정한 값을 나타낼 때 까지 monitoring
후 일정한 값을 유지할 때 약물을 처리하여 하층에 투과된 약물의 농도를 HPLC를
사용하여 측정
 Caco-2 세포 monolayer에서 세포막투과계수 (apparent membrane permeability
coefficient, Papp) 계산
※apical→basolateral 방향으로의 투과시험에서 C1은 apical side 중 시료의 초기농도를 의미
세포주를 사용한 투과성 실험 방법

14
Proposed Model Description: Apparent Permeability Coefficient (Papp)
(약물투과도시험법 개발에 관한 연구 보고서, 식품의약품안전청, 2004

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 장점
 세포의 apical표면에 많은 microvilli를 가지고 세포 사이의 tight junction을 형성하며,
여러 가지 transporter가 잘 발현되어 실제 장관세포와 유사성을 가져 세포레벨에서
약물의 투과성을 예측
 단점
 실제 소장 상피층은 goblet 세포, enteroendocrine 세포, M-세포 등으로 다양하게
구성되어 점액을 분비하는 특성을 가지는 반면 Caco-2 세포는 전적으로 흡수세포
로 구성되어 mucus layer 를 형성하지 못함

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 세포주 모델을 사용한 투과성 실험에서 인간의 장관세포와 보다 유사한 환경을 위해
Caco-2 세포의 단점을 개선
 HT-29 세포와 같은 mucin을 분비하는 특성을 가진 세포와 Caco-2 세포를 co-
culture하는 방법 보고되었다.
 HT-29 세포로부터 얻어지는 goblet 세포는 monolayer에서 배양이 가능하여 약물
투과연구에 사용될 수 있음
 흡수 세포와 goblet 세포를 동시에 배양하는 연구에서 tight junction을 이루어
monolayer를 형성
☞ Caco-2와 HT-29 세포의 co-culture를 통한 투과성을 비교실험
☞ 처리하는 시료에 따라 투과성 증가 혹은 감소에 다양한 결과
예1) fluoride를 시료로 사용한 실험에서 caco-2 세포를 단독으로 사용한 실험계에서 투과성이 2%인 반면
Caco-2 세포와 HT-29 세포를 50 : 50으로 사용한 실험계에서는 7.4%로 투과성이 증가하는 결과
예2) 정확하게 소장의 상피층과 유사한 실험계의 확립을 위해 transwell의 apical side에는 Caco-2 세포와
HT-29 세포를 배양하고, basolateral side에 M-cell을 유도시키는 raji B 세포를 배양하여 triple
co-culture방법으로 투과실험을 한 결과 morphology의 변화로는 세포막의 크기와 두께가 증가된 것
을 현미경을 통해 확인
예3) insulin을 시료로 사용한 투과성 실험에서 Caco-2 세포와 HT-29 세포를 co-culture한 실험계보다
raji B 세포를 추가한 triple co-culture 실험계에서 보다 높은 투과성 보임

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Cell lines used for intestinal permeability assessment

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Transport assay using Caco-2 cells on traswell insert

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Trans Epithelial Electrical Resistance (TEER)
Caco 2 Cells Permeability Assay

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Caco 2 Cell Permeability Assay

Solvent
(fixed volume)
Adding solute in small
incremental amounts
Vigorously
shaking
Undissolved
solute particles ?
Examine
visually
Yes
No
Total amount
added up
Estimated solubility
Semiquantitative determination:

Accurately Quantitative determination
Excess drug powder
150 mg/ml (15 %)
+ solvent
Ampul/vial
(2-5 ml)
Shaking at constant
temperature
(25 or 37 oC)
Membrane filter
0.45 mm
Determine the drug
concentration in the
filtrate
Determine the drug
filtrate
Determine the drug
filtrate
Membrane filter
0.45 mm
Membrane filter
0.45 mm
Same
concentration ?
The first few ml’s of the filtrates should be
discarded due to possible filter adsorption
Solubility
48 hr
72 hr
? hr

pH-Solubility Profile
Excess drug
powder
Stir in beaker
with distilled
water
Continuous
stirring of
suspension
Add
acid/base
Measure
pH of
suspension
Determine the
concentration
of drug in
the filtrate
SOLUBILITY pH
Filter Stirring

2 4 6 8 10 12 14
5
4
3
2
1
Indomethacin
(weak acid)
Chlorpromazine
(weak base)
Oxytetracycline
(amphoteric)
pH
Log
aqueous
solubility
(mmol)
pH-Solubility Profile
양쪽성(amphoteric) 물질
 산성과 염기성 모두로
반응하는 물질
 아미노산, 단백질

27
산성 약물 Vs 염기성 약물

28
Rebamipide (Pka 3.38 / Strong Acid)

29
Solubility-pH profiles of amino acids showing departures
from the ideal Henderson-Hasselbalch shape

30

31

32

33
What is dissolution test ?
Please refer to
dissolution
PPT material !

34

 To obtain good in vitro-in vivo dissolution rate correlation, the in vitro dissolution
must always be carried under sink conditions.
 This can be achieved in one or more of the following ways:
1. Bathing the dissolving solid in fresh solvent from time to time.
2. Increasing the volume of dissolution fluid.
3. Removing the dissolved drug by partitioning it from the aqueous phase of the
dissolution fluid into an organic phase placed either above or below the
dissolution fluid—for example, hexane or chloroform.
4. Adding a water miscible solvent such as alcohol to the dissolution fluid, or
5. By adding selected adsorbents to remove the dissolved drug.
The in vitro sink conditions are so maintained that Cb is always less than 10% of Cs
35

 The Noyes-Whitney’s equation assumes that the surface area of the dissolving solid
remains constant during dissolution, which is practically not possible for dissolving
particles.
 Hence, dissolution methods that involve use of constant surface area discs are employed
to determine the rate of dissolution.
 To account for the particle size decrease and change in surface area accompanying
dissolution, Hixson and Crowell’s cubic root law of dissolution is used:
Wo1/3 – W1/3 = Kt
 Wo = original mass of the drug
 W = mass of the drug remaining to dissolve at time t
 K= dissolution rate constant
Hixson and Crowell’s Equation
36

8) Drug stability
37

 Particle size and surface area of a solid drug are inversely related to each other.
 Smaller the drug particle, greater the surface area.
 Two types of surface area of interest can be defined:
 Absolute surface area which is the total area of solid surface of any particle
 Effective surface area which is the area of solid surface exposed to dissolution medium.
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Particle Size Vs Surface Area
39

x ½
x ½
x ½
perform 24 times…
To What Extent Can We Increase Surface Area?
2.0 cm3 of material - single cube with side length
of ca. 1.25 cm - divided 24 times will produce
enough 1 nm-sized cubes to completely cover a
rugby field in a single layer
Source: Adapted from work of Clayton Teague, National Nanotechnology Initiative (www.nano.gov)
Source: http://flickr.com/photos/learza/114576761/. This image is
licensed under Creative Commons Attribution ShareAlike 2.0 License.
40

1cm X1 cm X 6 = 6 cm2
0.5cm X 0.5 cm X 6 x 8 = 12 cm2
41

Calculation of the surface area generated during size reduction of a single cube

kS
dt
dC

)
( S
C
Vh
DS
dt
dC

(1)
(3)
(2)
x = 0 x = h
Undissolved
Solid
Cs
C
Bulk
Solution
Aqueous Diffusion Layer
Concentration
Rationale for Engineered Nanoparticles
in Drug Delivery
• For a freely soluble drug, S is not critical: large Cs  large k  large dC/dt
• For a poorly soluble drug, k is small  dC/dt is highly responsive to S
)
( S
C
Vh
DS
dt
dC

44

45
What is polymorphism?
Please refer to
polymorphism
PPT material !

Nano technology
Nano technology ?
46

 From the modified Noyes-Whitney equation, it is clear that larger the surface area,
higher the dissolution rate.
 Since the surface area increases with decreasing particle size, a decrease in particle size,
which can be accomplished by micronization , will result in higher dissolution rates.
 However, it is important to note that it is not the absolute surface area but the effective
surface area that is proportional to the dissolution rate.
 Greater the effective surface area, more intimate the contact between the solid surface
and the aqueous solvent and faster the dissolution.
 But it is only when micronization reduces the size of particles below 0.1 microns that
there is an increase in the intrinsic solubility and dissolution rate of the drug.
 The surface of such small particles has energy higher than the bulk of the solid
resulting in an increased interaction with the solvent.
 This is particularly true in case of drugs which are non-hydrophobic, for example,
micronization of poorly aqueous soluble drugs like griseofulvin, chloramphenicol and
several salts of tetracycline results in superior dissolution rates in comparison to the
simple milled form of these drugs.
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 Micronisation has in fact enabled the formulator to decrease the dose of certain drugs
because of increased absorption efficiency—for example, the griseofulvin dose was
reduced to half and that of spironolactone was decreased 20 times following
micronisation.
 However, in case of hydrophobic drugs like aspirin, phenacetin and phenobarbital,
micronisation actually results in a decrease in the effective surface area of such
powders and thus, a fall in the dissolution rate.
 Three reasons have been suggested for such an outcome —
1. The hydrophobic surface of the drug adsorbs air onto their surface which inhibit
their wettability.
2. The particles re-aggregate to form larger particles due to their high surface free
energy, which either float on the surface or settle at the bottom of dissolution medium.
3. Electrically induced agglomeration owing to surface charges prevents intimate
contact of the drug with the dissolution medium.
48

 The net result of these effects is that there is a decrease in the effective surface area
available to the dissolution medium and therefore a fall in the dissolution rate.
 The absolute surface area of hydrophobic drugs can be converted to their effective
surface area by:
1. Use of surfactant as a wetting agent that -
• Decreases the interfacial tension, and
• Displaces the adsorbed air with the solvent.
For example, polysorbate 80 increases the bioavailability of phenacetin by
promoting its wettability.
2. Adding hydrophilic diluents such as PEG, PVP, dextrose, etc. which coat the
surface of hydrophobic drug particles and render them hydrophilic.
49

 Particle size reduction and subsequent increase in the surface area and dissolution rate
is not advisable under following circumstances –
• When the drugs are unstable and degrade in solution form (penicillin G
and erythromycin),
• When drugs produce undesirable effects (gastric irritation caused by nitrofurantoin)
• When a sustained effect is desired.
 In addition to increasing the dissolution rate, the second mechanism by which a
reduction in particle size improves drug dissolution is through an increase in its
solubility.
 However, such an effect can only be achieved by reducing the particle size to a
submicron level which is possible by use of one of the following specialized techniques
such as formation of:
1. Molecular dispersion/solid solution where the sparingly soluble drug is molecularly
entrapped in the lattice of a hydrophilic agent such as cyclodextrins.
2. Solid dispersion where the drug is dispersed in a soluble carrier such as PVP,
PEG, urea, etc.
50

8) Drug stability
51

8) Drug stability
52

53
 Crystalline compounds can have various types of polymorphism including single entity
polymorph, solvates, salts, and co-crystals.
Schematic view of various types of solid forms
focusing on the internal structure (polymorphism)

54
Physicochemical and Pharmaceutical Properties of APIs
Influenced by Various Polymorphic Forms.

55
List of Various Drugs Studied for Polymorphism I

56
List of Various Drugs Studied for Polymorphism II

57
List of Various Drugs Studied for Polymorphism III

58
List of Various Drugs Studied for Polymorphism IV

59
List of Various Drugs Studied for Polymorphism V

60
List of Various Drugs Studied for Polymorphism VI

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List of Various Drugs Studied for Polymorphism VII

62
# : minimum number of known crystal structures / * : Room temperature
† : Unclassified / ‡ : Not reported.
Note: For the overall polymorphic forms, neither salts and solvates without pharmaceutical application
nor co-crystals were considered
List of Various Drugs Studied for Polymorphism VIII

Rational for choice/selection of the methods
for the preparation of polymorphs
63

64
(a) Number of different crystal structures (polymorphs when there are more than one structure)
(b) Types of solid forms expected to be present in the solid formulation
(c) Distribution in the BCS
(d) Distribution in the BCS indicating the APIs with high solubility (classes I/III) and
low solubility (classes II / IV)
Statistical features of the 65 APIs available as solid formulations

General Methods to Prepare Polymorphs
65

List of analytical techniques for polymorph characterization I
66

67
List of analytical techniques for polymorph characterization II

68
Comparison of mean blood serum levels after administration of chloramphenicol

69
The dissolution of theophylline monohydrate rising to an equilibrium
solubility

70
The dissolution behaviour for erythromycin as the anhydrate, monohydrate

71
The disruption of a crystal (represented as a brick wall) giving the possibility

 Depending upon the internal structure, a solid can exist either in a crystalline or
amorphous form
 When a substance exists in more than one crystalline form, the different forms are
designated as polymorphs and the phenomenon as polymorphism.
 Polymorphs are of two types:
1. Enantiotropic polymorph is the one which can be reversibly changed into
another form by altering the temperature or pressure e.g., sulphur, and
2. Monotropic polymorph is the one which is unstable at all temperatures and
pressures e.g., glyceryl stearates.
 The polymorphs differ from each other with respect to their physical properties such as
solubility, melting point, density, hardness and compression characteristics.
 They can be prepared by crystallizing the drug from different solvents under diverse
conditions.
 The existence of the polymorphs can be determined by using techniques such as optical
crystallography, X-ray diffraction, differential scanning calorimetry, etc
72

Classification of internal structure of a compound
73

 Depending on their relative stability, one of the several polymorphic forms will be
physically more stable than the others.
 Such a stable polymorph represents the lowest energy state, has highest melting point and
least aqueous solubility.
 The remaining polymorphs are called as metastable forms which represent the higher
energy state, have lower melting points and higher aqueous solubilities. Because of their
higher energy state, the metastable forms have a thermodynamic tendency to convert to
the stable form.
 A metastable form cannot be called unstable because if it is kept dry, it will remain stable
for years.
74

 Since the metastable forms have greater aqueous solubility, they show better
bioavailability and are therefore preferred in formulations
 for example, of the three polymorphic forms of chloramphenicol palmitate -A, B and C,
the B form shows best bioavailability, and the A form is virtually inactive biologically.
 The polymorphic form III of riboflavin is 20 times more water-soluble than the form I.
Only 10% of the pharmaceuticals are present in their metastable forms.
 However, because of their poor thermodynamic stability, aging of dosage forms
containing such metastable forms usually result in formation of less soluble, stable
polymorph
 for example, the more soluble crystalline form II of cortisone acetate converts to the
less soluble form V in an aqueous suspension resulting in caking of solid.
 Such a transformation of metastable to stable form can be inhibited by dehydrating
the molecule environment or by adding viscosity building macromolecules such as
PVP, CMC, pectin or gelatin that prevent such a conversion by adsorbing onto the
surface of the crystals.
75

 About 40% of all organic compounds can exist in various polymorphic forms.
 Seventy percent of the barbiturates and 65% of sulphonamides exhibit polymorphism.
 Barbital, methyl paraben and sulphapyridine can exist in as many as 6 polymorphic
forms and cortisone acetate in 8 forms.
 Some drugs can exist in amorphous form (i.e. having no internal crystal structure).
 Such drugs represent the highest energy state and can be considered as supercooled
liquids.
 They have greater aqueous solubility than the crystalline forms because the energy
required to transfer a molecule from crystal lattice is greater than that required for non-
crystalline (amorphous) solid
 Amorphous form of novobiocin is 10 times more soluble than the crystalline form.
 Chloramphenicol palmitate, cortisone acetate and phenobarbital are other examples
where the amorphous forms exhibit higher water solubility.
☞ The order for dissolution of different solid forms of drugs is —
Amorphous > Metastable > Stable.
76

4. Hydrates/Solvates (Pseudopolymorphism)
 The crystalline form of a drug can either be a polymorph or a molecular adduct or
both.
 The stoichiometric type of adducts where the solvent molecules are incorporated in the
crystal lattice of the solid are called as the solvates, and the trapped solvent as solvent
of crystallization.
 The solvates can exist in different crystalline forms called as pseudopolymorphs.
 This phenomenon is called as pseudopolymorphism.
 When the solvent in association with the drug is water, the solvate is known as
a hydrate. Hydrates are most common solvate forms of drugs.
77

 Generally, the anhydrous form of a drug has greater aqueous solubility than the
hydrates.
 This is because the hydrates are already in interaction with water and therefore have
less energy for crystal break-up in comparison to the anhydrates (thermodynamically
higher energy state) for further interaction with water.
 The anhydrous form of theophylline and ampicillin have higher aqueous solubilities,
dissolve at a faster rate and show better bioavailability in comparison to their
monohydrate and trihydrate forms respectively.
 On the other hand, the organic (nonaqueous) solvates have greater aqueous solubility
than the non-solvates
 for example, the n-pentanol solvate of fludrocortisone and succinylsulphathiazole and
the chloroform solvate of griseofulvin are more water-soluble than their non-solvated
forms.
 Like polymorphs, the solvates too differ from each other in terms of their physical
properties.
 In case of organic solvates, if the solvent is toxic, they are not of therapeutic use.
4. Hydrates/Solvates (Pseudopolymorphism)
78

5. Salt Form of the Drug
 Most drugs are either weak acids or weak bases.
 One of the easiest approaches to enhance the solubility and dissolution rate of such
drugs is to convert them into their salt forms.
 Generally, with weakly acidic drugs, a strong base salt is prepared such as the
sodium and potassium salts of barbiturates and sulphonamides.
 In case of weakly basic drugs, a strong acid salt is prepared like the hydrochloride
or sulphate salts of several alkaloidal drugs.
79

 At a given pH, the solubility of a drug, whether acidic/basic or its salt form is a constant.
 The influence of salt formation on the drug solubility, rate of dissolution and absorption
can be explained by considering the pH of the diffusion layer and not the pH of the bulk
of the solution (refer diffusion layer theory of drug dissolution). Consider the case of a
salt of a weak acid.
 At any given pH of the bulk of the solution, the pH of the diffusion layer (saturation
solubility of the drug) of the salt form of a weak acid will be higher than that observable
with the free acid form of the drug (can be practically observed in the laboratory).
 Owing to the increased pH of the diffusion layer, the solubility and dissolution rate of a
weak acid in this layer is promoted; since it is a known fact that higher pH favours the
dissolution of weak acids.
☞ If dissolution is faster, absorption is bound to be rapid.
 In case of salts of weak bases, the pH of the diffusion layer will be lower in comparison to
that found with the free base form of the drug.
☞ Solubility of a basic drug at this lower pH is enhanced
80

 [H+]d = hydrogen ion concentration of the diffusion layer
 [H+]b = hydrogen ion concentration of the bulk of the solution
for salts of weak acids, [H+]d < [H+]b
for salts of weak bases, [H+]d > [H+]b
81

 The increase and decrease in pH of the diffusion layer by the salts of weak acids and
bases have been attributed to the buffering action of strong base cation and strong acid
anion respectively.
 Yet another convincing reason for enhanced solubility of salts of weak acids is the
precipitation of the drug as very fine particles.
 When the soluble ionic form of the drug diffuses from the stagnant diffusion layer into
the bulk of the solution whose pH is low, it is transformed into its free acid form having
lesser aqueous solubility at the lower pH of the bulk solution.
 Consequently, this free acidic form of the drug is precipitated in the form of fine
particles.
 The resultant increase in the surface area is then responsible for the rapid dissolution
and absorption in comparison to the drug administered in just the acidic form
82

 The principle of in situ salt formation has been utilized to enhance the dissolution and
absorption rate of certain drugs like aspirin and penicillin from buffered alkaline
tablets.
 The approach is to increase the pH of the microenvironment of the drug by
incorporating buffer agents and promote dissolution rate.
 Apart from the enhanced bioavailability, buffered aspirin tablets have two more
advantages
 Firstly, the gastric irritation and ulcerogenic tendency of the drug is greatly reduced,
 Secondly, the problem with the use of sodium salt of aspirin (to enhance the solubility)
which otherwise has poor hydrolytic stability, is overcome by in situ salt formation.
84

 The selection of appropriate salt form for better dissolution rate is also important.
 It has been shown that the choline and the isopropanolamine salts of theophylline
dissolve 3 to 4 times more rapidly than the ethylenediamine salt and show better
bioavailability.
 A factor that influences the solubility of salt forms of the drug is the size of the counter
ion.
 Generally speaking, smaller the size of the counter ion, greater the solubility of salt
 Bioavailability of novobiocin from its sodium salt, calcium salt and free acid form was
found to be in the ratio — 50 : 25 : 1.
 Where the counter ion is very large in size and/or has poor ionic strength (as in the case
of ester form of drugs), the solubility may be much lower than the free drug itself
 The pamoates, stearates and palmitates of weak bases have poor aqueous solubility.
 These forms are, however, useful in several ways such as to prolong the duration of
action (steroidal salts), to overcome bad taste (chloramphenicol palmitate), to enhance
GI stability (erythromycin estolate) or to decrease the side effects, local or systemic.
85

 There are exceptions where the so called more soluble salt form of the drug
showed poor bioavailability.
 One such study was the comparative dissolution of sodium phenobarbital and
free phenobarbital from their tablets.
 Slower dissolution with sodium salt was observed and the reason attributed to it
was that its tablet swelled but did not disintegrate and thus dissolved slowly.
 An identical result was obtained with hydrochloride salts of several tetracycline
analogs and papaverine; better dissolution and bioavailability was observed
with the free bases.
 The reason for poor solubility and dissolution rate was the suppression action of
the common ion effect.
86

87
6. Drug pKa and Lipophilicity and GI pH
(pH Partition Hypothesis)

88
Acidic drug Vs Basic drug ?

89
pKa - Why most drugs are weak acids or weak bases - YouTube

90
 The pH partition theory (Brodie et al) explains in simple terms, the process of drug
absorption from the GIT and its distribution across all biological membranes.
 The theory states that for drug compounds of molecular weight greater than 100, which
are primarily transported across the bio membrane by passive diffusion,
 Process of absorption is governed by:
1. The dissociation constant (pKa) of the drug.
2. The lipid solubility of the unionized drug (a function of drug Ko/w).
3. The pH at the absorption site.

91
 Since most drugs are weak electrolytes (weak acids or weak bases), their degree of
ionization depends upon the pH of the biological fluid.
 If the pH on either side on the membrane is different, then the compartment whose pH
favours greater ionization of the drug will contain greater amount of drug, and only the
unionized or undissociated fraction of drug, if sufficiently lipid soluble, can permeate
the membrane passively until the concentration of unionized drug on either side of the
membrane becomes equal i.e. until equilibrium is attained.
The above statement of the hypothesis was based on the assumptions that:
1. The GIT is a simple lipoidal barrier to the transport of drug.
2. Larger the fraction of unionized drug, faster the absorption.
3. Greater the lipophilicity (Ko/w) of the unionized drug, better the absorption.

경구용 약물의 체내 동태 : 흡수(Absorption)

94
7. Drug pKa and Gastrointestinal pH
 The amount of drug that exists in unionised form is a function of dissociation constant
(pKa) of the drug and pH of the fluid at the absorption site.
 It is customary to express the dissociation constants of both acidic and basic drugs by
pKa values.
 The lower the pKa of an acidic drug, stronger the acid i.e. greater the proportion of
ionised form at a particular pH. Higher the pKa of a basic drug, stronger the base.
☞ From the knowledge of pKa of drug and pH at the absorption site (or biological fluid),
the relative amount of ionised and unionised drug in solution at a particular pH and
the percent of drug ionised at this pH can be determined by Henderson-Hasselbach
equations

95
For Weak Acids:
 Very weak acids (pKa > 8) such as phenytoin, ethosuximide and several barbiturates
are essentially unionised at all pH values and therefore their absorption is rapid and
independent of GI pH.
 Acids in the pKa range 2.5 to 7.5 are greatly affected by changes in pH and therefore
their absorption is pH-dependent; e.g. several NSAIDs like aspirin, ibuprofen,
phenylbutazone, and a number of penicillin analogs.
 Such drugs are better absorbed from acidic conditions of stomach (pH < pKa) where
they largely exist in unionised form.
 Stronger acids with pKa < 2.5 such as cromolyn sodium are ionised in the entire
pH range of GIT and therefore remain poorly absorbed.

96
For Basic Drugs:
 Very weak bases (pKa < 5.0) such as caffeine, theophylline and a number of benzo-
diazepines like diazepam, oxazepam and nitrazepam are essentially unionised at all pH
values and therefore their absorption is rapid and pH-independent.
 Bases in the pKa range 5 to 11.0 are greatly affected by changes in pH and hence
their absorption is pH-dependent; e.g. several morphine analogs, chloroquine,
amitriptyline.
 Such drugs are better absorbed from the relatively alkaline conditions of the intestine
where they largely exist in unionised form.
 Stronger bases with pKa > 11.0 like mecamylamine and guanethidine are ionised
in the entire pH range of GIT and therefore poorly absorbed.

97
Influence of drug pKa and GI pH on Drug Absorption

98
By using equations, one can calculate the relative amounts of unionised (absorbable) and
ionised (unabsorbable) forms of the drug and predict the extent of absorption at a given pH
of GIT.
Influence of pH on ionisation of drug.
[HA] and [BOH] are concentration of unionised acid and base, and [A-] and [B+] are
concentration of ionised acid and base respectively

99
 Besides the dissociation constant pKa, total aqueous solubility, ST, of an ionisable
drug is an important factor in the passive absorption of drugs.
 It is defined as the sum of concentration of ionised drug in solution and concentration
of unionised drug in solution.
 The solubility of unionised form of the drug is known as the intrinsic solubility of the
drug.
 If Sa is the intrinsic solubility of weakly acidic drugs and Sb that of weakly basic
drugs, then –for acidic drugs,

100
pH-solubility profile for a free acid and free base of weakly acidic and weakly basic drugs.
pH-solubility curve for weakly acidic and weakly basic drugs

101
 When the concentration of ionised and unionised drug becomes equal, the second
term of equations reduces to zero (since log 1 = zero), and thus pH = pKa.
 The pKa is a characteristic of the drug.

102

103
Henderson-Hasselbach equations

104

105

106

107

108

109

110

111

112
 As mentioned earlier, it is the pKa of a drug that determines the degree of ionization at a
particular pH and that only the unionized drug, if sufficiently lipid soluble, is absorbed
into the systemic circulation.
 Thus, even if the drug exists in the unionized form, it will be poorly absorbed if it has
poor lipid solubility (or low Ko/w). Ideally, for optimum absorption, a drug should have
sufficient aqueous solubility to dissolve in the fluids at the absorption site and lipid
solubility (Ko/w) high enough to facilitate the partitioning of the drug in the lipoidal bio
membrane and into the systemic circulation.
 In other words, a perfect hydrophilic-lipophilic balance (HLB) should be there in the
structure of the drug for optimum bioavailability.
Lipophilicity and Drug Absorption

113
 The lipid solubility of a drug is measured by a parameter called as log P where P is
oil/water partition coefficient (Ko/w or simply P) value of the drug.
 This value is a measure of the degree of distribution of drug between lipophilic solvents
such as n-octanol and an aqueous phase (water or a suitable buffer).
 In general, the octanol/pH 7.4 buffer partition coefficient value in the range of 1 to 2 of a
drug is sufficient for passive absorption across lipoidal membranes.
 A direct correlation between a drug’s Ko/w and extent of absorption is illustrated in
Table 2.6.
Lipophilicity and Drug Absorption

114
Comparison between Intestinal Absorption of Some Drugs through the Rat
Intestine and Ko/w of the Ionized Form of the Drugs

115
For ionisable drugs where the ionised species does not partition into the aqueous phase,
the apparent partition coefficient (D) can be calculated from following equations –
for acidic drugs,
log D = log P - log [1 + 10
(pH –pKa)
]
for basic drugs,
log D = log P - log [1 + 10
(pKa –pH)
]

116
The pH-partition hypothesis over-simplified the otherwise complicated process of drug
absorption and therefore has its own limitations.
Some of the deviations from the theory are:
1. Presence of virtual membrane pH
2. Absorption of ionised drug
3. Influence of GI surface area and residence time of drug
4. Presence of aqueous unstirred diffusion layer
Limitations of pH-Partition Hypothesis

117
1. Presence of Virtual Membrane pH:
 The pH-partition hypothesis suggested that only the unionized drug at a given GI lumen
pH is absorbed.
 An S-shaped curve, called as the pH-absorption curve denoting the dissociation of drug,
is obtained when pH is plotted versus rate of drug absorption
 However, differences in the extent of absorption of salicylic acid has been observed at a
given GI pH than that predicted by pH-partition hypothesis. The experimental pH-
absorption curves are less steep and shift to the left (lower pH values) for a basic drug
and to the right (higher pH values) for an acidic drug.
 This led to the suggestion that a virtual pH, also called as the microclimate pH, different
from the luminal pH exists at the membrane surface.
 This virtual membrane pH actually determines the extent of drug ionization and thus,
drug absorption.

118
pH-absorption curve for acidic and basic drugs.
Dotted lines indicate curves predicted by pH-partition hypothesis and bold lines indicate the practical curves.

119
2. Absorption of Ionised Drugs
 An important assumption of the theory was that only unionised form of the drug is
absorbed and permeation of the ionised drug is negligible since its rate of absorption is
3 to 4 times less than that of unionised drug.
 This is called as principle of non-ionic diffusion.
 The principle is true to a large extent as ionised drugs have low lipid solubility
and relatively poor permeability.
 However, the pH-absorption curve shift suggested that ionised forms of some drugs
also get absorbed to a considerable extent.
 If such drugs have a large lipophilic group in their structure, despite their ionisation,
they will be absorbed passively
 for example, morphinan derivatives.
 Other mechanisms are also involved in the absorption of ionised drugs such as active
transport, ion-pair transport and convective flow.

120
3. Influence of GI Surface Area and Residence Time of Drug
 According to the pH-partition theory, acidic drugs are best absorbed from stomach
(acidic pH) and basic drugs from intestine (alkaline pH) in which conditions they are
unionised to a large extent.
 This could be true under conditions where the surface area of stomach and intestine are
same.
 It could also mean that once an acidic drug reaches the intestine, the remaining fraction
will be poorly absorbed and that unless a basic drug reaches the intestine and gets
absorbed considerably, it may not be able to attain its therapeutic level.
 But, irrespective of the GI pH and the degree of ionization, both acidic and basic drugs
are more rapidly absorbed from the intestine, primarily because of its large surface area
and secondly, because of long residence time of the drug in the intestine.

121
4. Presence of Aqueous Unstirred Diffusion Layer
 The pH-shift in the absorption of acidic and basic drugs, as discussed earlier, also
accounts for the fact that the bulk of the luminal fluid is not in direct contact with the
membrane but a barrier called as aqueous unstirred diffusion layer is interposed between
them.
Presence of aqueous unstirred diffusion layer on the membrane surface

122
4. Presence of Aqueous Unstirred Diffusion Layer:
 Such a layer has a real thickness and is a barrier to absorption of drugs.
 In the original pH-partition theory, the rate-limiting step in the absorption of drugs was
the partitioning in the lipid barrier.
 With the incorporation of unstirred aqueous diffusion layer, a drug must diffuse first
through this aqueous barrier and then through the lipoidal barrier.
 Thus, drugs having large partition coefficient can rapidly penetrate the lipid membrane
but diffusion through unstirred water layer is the rate-limiting step in their absorption.
 This applies in particular to high molecular weight fatty acids and bile acids.
Despite its limitations, the pH-partition theory is still useful in the basic understanding of
drug absorption and movement of drug between various body compartments

123
 A drug for oral use may destabilize either during its shelf-life or in the GIT.
 Two major stability problems resulting in poor bioavailability of an orally administered
drug are—degradation of the drug into inactive form, and interaction with one or more
different component(s) either of the dosage form or those present in the GIT to form a
complex that is poorly soluble or is unabsorbable.
 Destabilization of a drug during its shelf-life and in the GIT will be discussed in detail
under formulation factors and patient related factors respectively.
Stereochemical Nature of Drug
 Chiral drugs constitute approximately 60% of the drugs in current use.
 Majority of these are marketed as racemic mixtures.
 Although it is well established that optical isomers differ in the potency of
pharmacological effect, it is only recently that attention is being paid to influence of
chirality on pharmacokinetic processes like absorption, distribution and elimination.
 As majority of drugs are absorbed passively, they do not display stereoselectivity.
 Conversely, demonstration of stereoselective absorption would be strong evidence that a
drug is absorbed by a carrier-mediated process.
8. Drug Stability

124
별첨자료 Drug Absorption
&
Formulation

별첨자료 I
Drug Absorption & Formulation

생체이용율(Bioavailability)

혈중 프로파일(plasma profile)
Cmax
Tmax
시간(hr)

Factors Affecting Drug Absorption

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