Transcript chapter 3

3. Dosage Form Design:
Pharmaceutic and Formulation
Considerations
Contents
1.
2.
3.
4.
The need for dosage forms
General considerations in dosage
form design
Drug and drug product stability
Pharmaceutical ingredients
nonmedical
agents,
referred to as
pharmaceutic
ingredients
Drug substances are seldom administered alone
The pharmaceutic ingredients
 solubilize,
 suspend,
 thicken
 dilute
 emulsify
 stabilize
 preserve
 color
 flavor
The general area of study concerned with the
 formulation
Physical
 manufacture
Chemical
Biological characteristics
 stability
Compatible
 effectiveness
of pharmaceutical dosage forms.
A drug product
 stable
 efficacious
 attractive
 easy to administer
 safe
 manufactured under appropriate measures
of quality control
1. The need for dosage forms
Besides providing the
mechanism for the safe and
convenient delivery of
accurate dosage, dosage
forms are needed for
additional reasons:
1) Protection from oxygen and
humidity (coated tablets,
sealed ampuls)
2) Protection from gastric
acid after oral
administration (entericcoated tablets)
3) To conceal the bitter,
salty, or offensive taste
or odor of a drug
substance (capsules,
coated tablets, flavored
syrups)
4)
Liquid
preparation
insoluble
unstable
in the desired vehicle
Suspension
5)
Clear liquid dosage forms
Syrups
solutions
6) To provide rate-controlled drug
action (various controlled-release
tablets, capsules and suspensions)
7) To provide topical drug action
from topical administration sites
(ointments, creams, transdermal
patches, ophthalmic, ear, and nasal
preparations)
8) To provide for the
insertion of a drug into
one of the body’s
orifices (e.g., rectal or
vaginal suppositories)
9) To provide for the
placement of drugs
directly into the
bloodstream or into
body’s tissues (e.g.,
injections)
10) To provide for topical
drug action through
inhalation therapy
(e.g., inhalants and
inhalation aerosols)
2. General considerations in dosage
form design
Desired features
 Drug release profile
 Bioavailability
 Clinical effectiveness
Factors considered

the nature of illness
the manner in which it is treated
age
anticipated condition of the patient

Because they plays a role in dosage form design



Preformulation studies
1)
Before the formulation of a drug substance into
a dosage form, it is essential that it will be
chemically and physically characterized.
Physical description
The majority of drug substances in use today
occur as solid materials. Most of them are pure
chemical compounds of either crystalline or
amorphous constitution.


A crystal or crystalline solid is a solid
material whose constituent atoms,
molecules, or ions are arranged in an orderly
repeating pattern extending in all three
spatial dimensions.
An amorphous solid is a solid in which there
is no long-range order of the positions of
the atoms.

The purity of the chemical substance is
essential for its identification as well as for
the evaluation of its chemical, physical, and
biologic properties.
Chemical properties
Physical properties
Structure,
form and reactivity
Physical description,
Particle size,
Crystalline structure,
Melting point,
Solubility
Biologic properties
Ability to get to a site
of action,
Elicit a biologic response
Drugs can be used therapeutically as solids,
liquids and gases. Liquids drugs are used to
a much lesser extent than solid drugs; gases,
even less frequently.



Many of the liquids are volatile substances
and as such must be physically sealed from
the atmosphere to prevent their loss.
Another problem associated with liquid
drugs is that those intended for oral
administration
cannot
generally
be
formulated into tablet form.
Formulation and stability difficulties arise
less frequently with solid dosage forms than
with liquid pharmaceutical preparations.
2) Microscopic examination
 Microscopic examination of the raw drug
substance is an important step in
preformulation work.

It gives an indication of particle size and
particle size range of the raw material as
well as the crystal structure.
3) Melting point depression
 A characteristic of a pure substance is a
defined melting point or melting range. If
not pure, the substance will exhibit a
depressed melting point.

This phenomenon is commonly used to
determine the purity of a drug substances
before inclusion in the same dosage form.
The melting point, or freezing point, of a
pure crystalline solid is defined as that
temperature where the pure liquid and solid
exist in equilibrium.
（纯净的结晶性固体的熔点或冰点系指纯液
体和固体达到平衡时的温度。）
 The melting point/range of a drug can be
used as an indicator of purity of chemical
substances (a pure substance would
ordinarily be characterized by a very sharp
melting peak).


An altered peak or a peak at a different
temperature may be indicative of an
adulterated or impure drug.
（峰形的改变或熔点峰温度的差异表示药物
混杂其他物质或不纯）
The addition of a second component to a pure
compound (A), resulting in a mixture, will result in
a melting point that is lower than that of the pure
compound.
The degree to which the melting point is lowered
is proportional to the mole fraction (NA) of the
second component that is added. This can be
expressed as:
T=2.303RTT0logNA/Hf
Hf is the molar heat of fusion
T is the absolute equilibrium temperature
T0 is the melting point of pure A, and
R is the gas constant
Two things are noteworthy in contributing
to the extent of melting-point lowering.
① Evident from this relationship is the
inverse proportion between the melting
point and the heat of fusion.
- When a second ingredient is added to a
compound with a low molar heat of fusion,
a large lowering of the melting point is
observed;
- Substances with a high molar heat of fusion
will show little change in melting point with
the addition of a second compound.
② The extent of lowering of the melting point
is also related to the melting point itself.
- Compounds with low melting points are
affected to a greater extent than compounds
with high melting points upon the addition
of a second component
- Low-melting-point compounds will result in
a greater lowering of the melting point than
those with high melting points.
4) The phase rule （相律）
Phase diagrams are often constructed to
provide a visual picture of the existence and
extent of the presence of solid and liquid
phases in binary, ternary and other mixtures.
(相图是通常用于解释和表达固相与液相以
二元、三元混合时其存在和范围的可视图
画。）

A phase diagram, or temperaturecomposition diagram, represents the
melting point as a function of composition
of two or three component systems.
（相图或温度成分图表示二或三组分系统其
组成与熔点的关系）

T
IV
II
III
I

Each phase is a
homogenous part of the
system, physically
separated by distinct
boundaries.
A description of the
conditions under which
these phases can exist is
called the Phase Rule,
which can be presented
as: F=C-P+X
F=C-P+X
where F is the number of degrees of freedom （自
由度数）.The degrees of freedom represent the
environment conditions which can be
independantly varied without changing the
number of phases in the system.
C is the number of components （化合物数）,
P is the number of phases （相数）,
X is a variable dependent upon selected
considerations of the phase diagram (1, 2 or 3)
（变量，取决于相图选择的部分）
5) Particle size
Certain physical and chemical properties of
drug substances are affected by the particle
size distribution, including drug dissolution
rate, bioavailability, content uniformity, taste,
texture, color and stability.
In addition, properties such as flow
characteristics and sedimentation rates,
among others, are also important factors
related to particle size.
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Of specical interest is the effect of particle
size on the drug’s absorption
griseofulvin
nitrofurantoin
spironolactone
procaine penicillin
6) Polymorphism
 An important factor on formulation is the
crystal or amorphous form of the drug
substance.
 Polymorphic forms usually exhibit different
physical-chemical properties including melting
point and solubility.
 The changes in crystal characteristics can
influence bioavailability, chemical and physical
stability, and have important implications in
dosage form process functions.
Crystal structure
Polymorphism
Solvate form
Bioavailability
Chemical and physical stability
Dosage form process functions
Hot stage microscopy
Thermal analysis
Infrared spectroscopy
X-ray diffraction
Tableting
process (flow,
compaction
behaviour)
7) Solubility
 A drug must possess some aqueous
solubility for therapeutic efficacy.
 For a drug to enter the systemic circulation
to exert a therapeutic effect, it must first be
in solution.
 Relatively
insoluble compounds often
exhibit incomplete or erratic absorption.
 If the solubility of the drug substance is less
than desirable, consideration must be given
to improve its solubility.
8) Solubility and particle size
Although solubility is normally considered a
physicochemical constant, small increases in
solubility can be accomplished by particle
size reduction.
The particle size and surface area of a drug exposed
to a medium can affect actual solubility, within
reason. For example, in the following relationship:
logS/S0=2V/(2.303RTr)
Where S is the solubility of the small particles,
S0 is the solubility of the large particles,
 is the surface tension
V is the molar volume
R is the gas constant
T is the absolute temperature
r is the radius of the small particles
9) Solubility and pH
 pH is one of the most important factors
involved in the formulation process.
 Two areas of critical importance are the
effects of pH on solubility and stability.
 The effect of pH on solubility is critical in
the formulation of liquid dosage forms,
from oral and topical solutions to
intravenous solutions and admixtures.


The solubility of a weak acid or base is often
pH dependent.
The total quantity of a monoprotic weak
acid (HA) in solution at a specific pH is the
sum of the concentrations of both the free
acid and salt (A-) forms. The expression is:
Ka
HA
H++Awhere Ka is the dissociation constant.
There may be a certain pH level reached
where the total solubility (ST) of the drug
solution is saturated with respect to both the
salt and acid forms of the drug, i.e., the
pHmax
(当达到某一pH时，药物溶液中药物盐型和
酸型的总溶解度达到饱和，即为pHmax).


The solution can be saturated with respect
to the salt at pH values higher than this, but
not with respect to the acid.
At pH values less than this, the solution can
be saturated with respect to the acid, but not
to the salt.
(在pH高于该值时，溶液被盐型饱和；而pH
低于该值时，溶液被酸型而不是盐型饱和）
To calculate the total quantity of drug that
can be maintained in solution at a selected
pH, two different equations can be used,
depending on whether the product is to be
in a pH region above or below the pHmax
when below the pHmax
ST=Sa(1+Ka/H+)
when above the pHmax
ST=S’a(1+H+/Ka)
Where Sa is the saturation solubility of the
free acid, S’a is the saturation solubility of
the salt form.
10) Dissolution



Dissolution rate can affect the onset, intensity, and
duration of response, and control the overall
bioavailability of the drug from the dosage form.
The dissolution rate of drugs may be increased by
decreasing the drug’s particle size.
It may also be increased by increasing its solubility
in the diffusion layer. The most effective means of
obtaining higher dissolution rates is to use a highly
water soluble salt of the parent substance.


Fick’s laws of diffusion and the NoyesWhitney equation
When individual molecules move within a
substance, diffusion is said to occur. This may
occur as the result of a concentration gradient
or by random molecular motion.
Fick’s First Law involving steady-state
diffusion (where dc/dx does not change) is
derived from the following expression for the
quantity of material (M) flowing through a
cross-section of a barrier (S) in unit time (t)
expressed as the flux (J)
J=dM/(Sdt)
Under a concentration gradient (dc/dx), Fick’s
First Law can be expressed as
J=D(C1-C2)/h or J=-D(dC/dx)
where J is the flux of a component across a plane
of unit area,
C1 and C2 are the concentrations in the donor and
receptor compartments,
h is the membrane thickness,
D is the diffusion coefficient (or diffusivity).
The sign is negative denoting that the flux is in the
direction of decreasing concentration.
To study the rate of change of the drug in
the system, one needs an expression that
relates the change in concentration with
time at a definite location in place of the
mass of drug diffusing across a unit area of
barrier in unit time, this expression is known
as Fick’s Second Law.
（为了研究药物在系统中改变的速率，需要
一个表达式来表达药物在单位时间内扩散
透过某一屏障的单位面积的浓度与时间的
关系，这个表达式即Fick第二定律。）
This law can be summarized as it states that
the change in concentration in a particular
place with time is proportional to the change
in concentration gradient at that particular
place in the system.
(这个定律可简述为在某一部位的浓度经时
间变化与系统中在该部位的浓度梯度变化
成比例。）
The concentration of drug in the membrane can
be calculated using the partition coefficient (K)
and the concentration in the donor and receptor
compartments
K=C1/Cd=C2/Cr
The expression can be written
dM/dt=DSK(Cd-Cr)/h
or, in sink conditions,
dM/dt=DSKCd/h=PSCd
The permeability coefficient (cm/sec) can be
obtained by rearranging to
P=DK/h

In the dissolution of particles of drug, the
dissolved molecules diffuse away from the
individual particle body. An expression to
describe this was derived from Fick’s
equations and is known as the Noyes and
Whitney expression. It can be written as
follows:
dC/dt =(DS/h)(Cs-C)
where C is the concentration of drug
dissolved at time t,
D is the diffusion coefficient of the solute in
solution,
S is the surface area of the exposed solid
h is the thickness of the diffusion layer
Cs is the saturation solubility of the drug
k=DS/h
dc/dt=k (Cs-C)
11) Membrane permeability
 To produce a biological response, the drug
molecule must first cross a biological
membrane.
 The biological membrane acts as a lipid
barrier to most drugs and permits the
absorption of lipid soluble substances by
passive diffusion while lipid insoluble
substances can diffuse across the barrier
only with considerable difficulty.




Specifically, pKa, solubility, and dissolution rate
provide an indication of absorption expectations.
To enhance these data, a technique using the
“everted intestinal sac”（体外小肠实验技术）
may be used in evaluating absorption
characteristics of drug substances.
Through this method, both passive and active
transport can be evaluated.
In the later stages of preformulation testing, in
vitro/in vivo correlation will be studied.
12) Partition coefficient
 In formulation development, the octanol-water
partition coefficient is commonly used.
 Following the illustrations provided above, it is
defined as
P=(Conc. of drug in octanol)/(Conc. of drug in
water)
P is dependent on the drug concentration only
if the drug molecules have a tendency to
associate in solution.
For an ionizable drug, the following equation
is applicable:
P=(Conc. of drug in octanol)/1-(Conc. of
drug in water)
where  equals the degree of ionization.
13) pKa/Dissociation constants
 Extent of ionization has an important effect
on the formulation and pharmcokinetic
parameter of the drug.
 The extent of dissociation/ionization is, in
many cases, highly dependent on the pH of
the medium containing the drug.
 In the pharmacokinetic area, the extent of
ionization of a drug is an important factor
of its extent of absorption, distribution, and
elimination.
Dissolution constant or pKa is usually
determined by potentiometric titration.
(解离常数或pKa通常可由电位滴定法测
定）。
Drug and drug product stability
1)
-
-
One of the most important activities of
preformulation work is the evaluation of the
physical and chemical stability of the pure
drug substance.
Drug stability: mechanisms of degradation
Chemical instability of medicinal agents may
take many forms.
The most frequently encountered destructive
processes are hydrolysis and oxidation.

Hydrolysis is a solvolysis process in which
(drug) molecules interact with water
molecules to yield breakdown products of
different chemical constitution.

A great number of medicinal agents are
esters or contain such other groupings as
substituted amides（酰胺）, lactones（内
酯）, and lactams （内酰胺）, which are
susceptible to the hydrolytic process.
一、水解

水解是药物降解的主要途径，属于这类降
解的药物主要有酯类（包括内酯）、酰胺
类（包括内酯类）。
1. 酯类药物的水解

含有酯键药物的水溶液，在H+或OH-或广义酸碱的
催化下，水解反应加速。特别在碱性溶液中，由
于酯分子中氧的负电性比碳大，故酰基被极化，
亲核性试剂OH-易于进攻酰基上的碳原子，而使酰
-氧键断裂，生成醇和酸，酸与OH-反应，使反应
进行完全。



盐酸普鲁卡因的水解可作为这类药物的代表，水解
生成对氨基苯甲酸与二乙胺基乙醇。还有盐酸可卡
因、普鲁本辛、硫酸阿托品、氢溴酸后马托品等。
羟苯甲酯类也有水解的可能。
酯类水解，往往使溶液的pH下降，有些酯类药物灭
菌后pH下降，即提示有水解可能。
内酯与酯一样，在碱性条件下易水解开环。硝酸毛
果芸香碱、华法林钠均有内酯结构，可以产生水解。
2. 酰胺类药物的水解

酰胺类药物水解以后生成酸与胺。属这
类的药物有氯霉素、青霉素类、头孢菌
素类、巴比妥类等药物。此外如利多卡
因、对乙酰氨基酚（扑热息痛）等也属
此类药物。
（1）氯霉素

氯霉素水溶液在pH7以下，主要是酰胺水解，
生成氨基物与二氯乙酸。
O2 N
H NHCOCHCl2
C C CH2OH
OHH
O2N
H NH2
C C CH2OH + CHCl2COOH
OHH
pH的影响：
 pH2~7， pH对水解速度影响不大；
 pH 6 ， 最稳定；
 pH<2 or pH>8，水解加速 。
脱氯的水解作用
（1）氯霉素
温度的影响

氯霉素水溶液120C加热，氨基物可能进
一步发生分解生成对硝基苯甲醇。
光的影响

水溶液对光敏感，在pH 5.4暴露于日光
下，变成黄色沉淀。
氯霉素的有些分解产物可能是发生氧化、
还原和缩合反应产生的。
（2）青霉素和头孢菌素类

青霉素类药物的分子中存在着不稳定的
-内酰胺环，在H+或OH-影响下，很易裂
环失效。如氨苄青霉素在酸、碱性溶液
中，水解产物为氨苄青霉酰胺酸。

头孢菌素类药物由于分子中同样含有内酰胺环，易于水解。如头孢唑啉在酸
与碱中都易水解失效。
（3）巴比妥类

也属于酰胺类药物，在碱性溶液中容
易水解。

有些酰胺类药物，如利多卡因，临近
酰胺基有较大的基团，由于空间效应，
故不易水解。
3. 其他药物的水解

阿糖胞苷在酸性溶液中，脱氨水解为阿
糖脲苷。在碱性溶液中，嘧啶环破裂，
水解速度加快。
O
NH2
HN
N
H
O
N
OH
O

CH2OH
+
O
N
CH2OH
HO
O
另外，如维生素B、地西泮、碘苷等药物
的降解，主要也是水解作用。

Another destructive process is oxidation.
The oxidative process is destructive to many
drug types, including aldehydes, alcohols,
phenols, sugars, alkaloids, and unsaturated
fats and oils.

Many of the oxidative changes in
pharmaceutical preparations have the
character of autoxidations.

Autoxidations occur spontaneously under
the initial influence of atmospheric oxygen
and proceed slowly at first and then more
rapidly as the process continues.
二、氧化

氧化也是药物变质最常见的反应。失去电子为氧
化，在有机化学中常把脱氢称氧化。药物氧化分
解常是自动氧化。即在大气中氧的影响下进行缓
慢的氧化过程。

药物的氧化作用与化学结构有关，许多酚类、烯
醇类、芳胺类、吡唑酮类、噻嗪类药物较易氧化。
药物氧化后，不仅效价损失，而且可能产生颜色
或沉淀。有些药物即使被氧化极少量，亦会色泽
变深或产生不良气味，严重影响药品的质量，甚
至成为废品。

氧化过程一般都比较复杂，有时一个药物，氧化、
光化分解、水解等过程同时存在。
1.酚类药物

这类药物分子中具有酚羟基，如肾上腺素、左
旋多巴、吗啡、去水吗啡、水杨酸钠等。
2.烯醇类

维生素C是这类药物的代表，分子中含有烯醇基，极易氧
化，氧化过程较为复杂。在有氧条件下，先氧化成去氢
抗坏血酸，然后经水解为2、3二酮古罗糖酸，此化合物
进一步氧化为草酸与L-丁糖酸。

在无氧条件下，发生脱水作用和水解作用生成呋喃甲醛
和二氧化碳，由于H+的催化作用，在酸性介质中脱水作用
比碱性介质快，实验中证实有二氧化碳气体产生。
3.其他类药物

芳胺类如磺胺嘧啶钠。吡唑酮类如氨基比
林、安乃近。噻嗪类如盐酸氯丙嗪、盐酸
异丙嗪等。这些药物都易氧化，其中有些
药物氧化过程极为复杂，常生成有色物质。
含有碳-碳双键的药物如维生素A或D的氧化，
是典型的游离基链式反应。

易氧化药物要特别注意光、氧、金属离子
对他们的影响，以保证产品质量。
三、其他反应
1.异构化

异 构 化 一 般 分 光 学 异 构 (optical
isomerization) 和 几 何 异 构 (geometric
isomerization)二种。

通常药物异构化后，生理活性降低甚至
没有活性。
（1）光学异构化

光学异构化可分为外消旋化作用
(racemization)和差向异构
(epimerization)。

左旋肾上腺素具有生理活性，本品水溶液在
pH 4左右产生外消旋化作用，外消旋以后，
只有50%的活性。因此，应选择适宜的pH。
左旋莨菪碱也可能外消旋化。外消旋化反应
经动力学研究系一级反应。
（1）光学异构化

差向异构化指具有多个不对称碳原子上的
基团发生异构化的现象。四环素在酸性条
件下，在4位上碳原子出现差向异构形成4
差向四环素，治疗活性比四环素低。毛果
芸香碱在碱性pH时，a-碳原子也存在差向
异构化作用，生成异毛果芸香碱，为伪一
级反应。麦角新碱也能差向异构化，生成
活性较低的麦角袂春宁(ergometrinine)。
（2）几何异构化

有些有机药物，反式异构体与顺式几何
异构体的生理活性有差别。维生素A的活
性形式是全反式(all-trans)。在多种维
生素制剂中，维生素A除了氧化外，还可
异构化，在2, 6位形成顺式异构化，此
种异构体的活性比全反式低。
2.聚合(polymerization)

聚合是两个或多个分子结合在一起形成的复杂
分子。

已经证明氨苄青霉素浓的水溶液在贮存过程中
能发生聚合反应，一个分子的-内酰胺环裂开
与另一个分子反应形成二聚物。此过程可继续
下去形成高聚物。据报告这类聚合物能诱发氨
苄青霉素产生过敏反应。

噻替派在水溶液中易聚合失效，以聚乙醇400
为溶剂制成注射液，可避免聚合，使本品在一
定时间内稳定。
3.脱羧

对氨基水杨酸钠在光、热、水分存在的条件
下很易脱羧，生成间氨基酚，后者还可进一
步氧化变色。

普鲁卡因水解产物对氨基苯甲酸，也可慢慢
脱羧生成苯胺，苯胺在光线影响下氧化生成
有色物质，这就是盐酸普鲁卡因注射液变黄
的原因。

碳酸氢钠注射液热压灭菌时产生二氧化碳，
故溶液及安瓿空间均应通以二氧化碳。
2) Drug and drug product stability: kinetics
and shelf-life
There are five types of stability of concern:
① Chemical
Each active ingredient retains its chemical
integrity and labeled potency, within the
specified limits.(shelf life)
② Physical
The original physical properties, including
appearance,
palatability,
uniformity,
dissolution and suspendability are retained.
③ Microbiologic
Sterility or resistance to microbial growth is
retained according to the specified
requirements. Antimicrobial agents that are
present retain effectiveness within specified
limits.
④ Therapeutic
The therapeutic effect remains unchanged.
⑤ Toxicologic
No significant increase in toxicity occurs.



Stability and expiration dating are based on
reaction kinetics, i.e.,
the study of the rate of chemical change
the way this rate is influenced by conditions
of concentration of reactants, products, and
other chemical species that may be present,
and by factors such as solvent, pressure, and
temperature.
In considering chemical stability of a
pharmaceutical, one must know the reaction
order and reaction rate.
3) Rate reactions
 The reaction rate expression is a description
of the drug concentration with respect to
time.
 Most commonly, zero-order and first-order
reactions are encountered in pharmacy.
Zero order rate reactions
If the loss of drug is independent of the
concentration of the reactants and constant
with respect to time (i.e., 1mg/ml/hour), the
rate is called zero order. The mathematical
expression is: -dC/dt=k0
where k0 is the zero-order rate constant
[concentration(C)/time(t)]
The integrated, and more useful form of the
equation, is: C=-k0t+C0

A drug suspension (125mg/ml) decays by
zero-order kinetics with a reaction rate
constant of 0.5 mg/ml/hour. What is the
concentration of intact drug remaining after
3 days (72 hours)?
C=-k0t+C0

How long will it take for the suspension to
reach 90% of its original concentration?
First order rate reactions
If the loss of drug is directly proportional to
the concentration remaining with respect to
time, it is called a first-order reaction and has
the units of reciprocal time, i.e., time-1. the
mathematical expression is
-dC/dt=kC
where C is the concentration of intact drug remaining,
t is time,
(-dC/dt) is the rate at which the intact drug degrades,
k is the specific reaction rate constant.
The integrated and more useful form of the
equation is
logC=-kt/2.303+logC0
where C0 is the initial concentration of the
drug.
In nature log form, the equation is
lnC=-kt+lnC0
4) Q10 method of shelf-life estimation
The Q10 method of shelf-life estimation
allows the pharmacist quickly to calculate
estimates of shelf-life for a product that may
have been stored or is going to be stored
under a different set of conditions.
The Q10 approach, based on Ea, is
independent of reaction order and is
described as:
Q10=e{(Ea/R)[1/(T+10)-(1/T)]}
where Ea is the energy of activation,
R is the gas constant, and
T is the absolute temperature.
In usable terms, Q10 is the ratio of two
different reaction rate constants, is defined
as
Q10=K(T+10)/KT

The equation to use for Q10 shelf-life estimates is
t90(T2)=t90(T1)/Q10(T/10)
where
t90(T2) is the estimated shelf-life
t90(T1) is the given shelf-life at a given
temperature,
T is the difference in the temperature T1 and T2
As is evident from this relationship, an increase in
T will decrease the shelf-life and a decrease in
T will increase shelf-life.
Buffer Capacity
pH,buffers, and buffer capacity are especially
important in drug product formulation, since
they affect the drug’s solubility, absorption,
and stability and the patient’s comfort.
pH=pKa+log(base/acid)
The ability of a buffer solution to resist changes in
pH upon the addition of an acid or a base is called
buffer capacity(β) and is defined thus:
β=△B/ △pH
△B is molar concentration of acid or base added
△pH is change in pH due to addition of acid or base,
And can be determined experimentally or calculated using the
Henderson-Hasselbach equation
5) Enhancing stability of drug products
There are several approaches to the
stabilization of pharmaceutical preparations
containing drugs subject to deterioration by
hydrolysis.
- the reduction and the elimination of water
from the pharmaceutical system,
This may be accomplished by applying a
waterproof protective coating over tablets or
by enclosing and maintaining the drug in
tightly closed containers.


In liquid preparations, water can frequently
be replaced or reduced in the formulation
through the use of substitute liquids such as
glycerin, propylene glycol, and alcohol.
In certain injectable products, anhydrous
vegetable oils may be used as the drug’s
solvent to reduce the chance of hydrolytic
decomposition.


For certain unstable antibiotic drugs, when an
aqueous preparation is desired, the drug may
be supplied to the pharmacist in a dry form for
reconstitution by adding a specified volume of
purified water just before dispensing.
For most hydrolyzable drugs the pH of
optimum stability is on the acid side,
somewhere between pH5 and 6.
Therefore, through judicious use of buffering
agents, the stability of otherwise unstable
compounds can be increased.


The oxidative process is diverted, and the
stability of the drug is preserved by agents
called antioxidants, which react with one or
more compounds in the drug to prevent
progress of the chain reaction.
Various antioxidants are employed in
pharmacy. Among those more frequently
used in aqueous preparations are sodium
sulfite (Na2SO3), sodium bisulfite (NaHSO3),
hypophosphorous acid (H3PO2), and
ascorbic acid.


Because the stability of oxidizable drugs
may be adversely affected by oxygen, certain
pharmaceuticals may require an oxygen-free
atmosphere during their preparation and
storage.
Oxygen-sensitive drugs may be prepared in
the dry state and they, as well as liquid
preparations, may be packaged in sealed
containers with the air replaced by an inert
gas such as nitrogen.

Stability Testing
3. Pharmaceutical ingredients





To prepare a drug substance into a final
dosage form, pharmaceutical ingredients
are required.
Solvents
To dissolve the drug substance
Flavors and sweeteners To make the product
more palatable
Colorants
To enhance product appeal
Preservatives To prevent microbial growth
Stabilizers To prevent drug decomposition




Diluents or fillers
To increase the bulk of the formulation
Binders
To cause the adhesion of the powdered drug
and pharmaceutic substances
Lubricants
To assist the smooth tableting process
Disintegrating agents
To promote tablet break-up after
administration
1) Handbook of pharmaceutical excipients
which presents monographs (专论) on over
200 excipients used in pharmaceutical
dosage form preparation.
 Nonproprietary （ 非 专 利 名 ） , chemical,
and commercial names,
 Empirical(经验的) and chemical formulas
and molecular weight,
 Pharmaceutical specifications and chemical
and physical properties,



Incompatibilities and interactions with other
excipients and drug substances,
Regulatory status,
Applications in pharmaceutic formulation or
technology.
2) Appearance and palatability
 Modern
pharmaceutical
preparations
present drug substances to the patient as
colorful, flavorful formulations attractive to
the sight, smell, and taste.
 An appropriate drug will have its most
beneficial effect when it is accepted and
taken properly by the patient. The proper
combination of flavor, fragrance, and color
in a pharmaceutical product contributes to
its acceptance.
3) Coloring
 Coloring agents are used in pharmaceutical
preparations for purposes of esthetics（美
学）.
 Most pharmaceutical colorants in use today
are of synthetic origin, a few are obtained
from natural mineral and plant sources.
 A color additive must be safe. In the case of
pharmaceutical preparations, color additives
must not interfere with the therapeutic efficacy
of the product in which they are used.

Dyes generally are added to pharmaceutical
preparations in the form of diluted solutions
(0.0005 and 0.001%) rather than as
concentrated dry powders. This permits
greater accuracy in measurement and more
consistent color production.
A formulation pharmacist must select the dyes
to be used in a particular formula on the basis
of the physical and chemical properties of the
dyes available.



Another important consideration when
selecting a dye for use in a liquid
pharmaceutical is the pH and pH stability of
the preparation to be colored.
The dye also must be chemically stable in the
presence of the other formulative ingredients
and must not interfere with the stability of the
other agents.
Dyes must also be reasonably photostable.
4) Preservatives
 Some types of pharmaceutical products like
ophthalmic and injectable preparations are
sterilized by physical methods.
Autoclaving for
 20 minutes at 15 pounds pressure and 121oC,
dry heat at 180oC for 1 hour,
 by bacterial filtration.



Other types of preparations such as syrups,
emulsions, suspensions and some semisolid
preparations, particularly creams that are not
sterilized during their preparation.
They are protected by the addition of an
antimicrobial preservative.
Most alcohol-containing pharmaceuticals such as
elixirs（酏剂）, spirits, and tinctures（酊剂系指
药物用规定浓度的乙醇浸出或溶解而制成的澄清
液体制剂，亦可用流浸膏稀释制成。供口服或外
用 ） are self-sterilizing and do not require
additional preservation.
General preservative considerations
 Only the undissociated fraction or molecular
form of a preservative possesses preservative
capability, because the ionized portion is
incapable of penetrating the microorganism.
 The preservative selected must be largely
undissociated at the pH of the formulation
being prepared.
Mode of action
Preservatives interfere with microbial growth,
multiplication, and metabolism through one or
more of the following mechanisms:
-
-
Modification of cell membrane permeability
and leakage of cell constituents (partial lysis)
Lysis and cytoplasmic leakage
Irreversible coagulation of cytoplasmic
constituents (e.g., protein precipitation)
-
-
-
Inhibition of cellular metabolism as through
interference with enzyme systems or
inhibition of cell wall synthesis
Oxidation of cellular constituents
hydrolysis
Preservative utilization
Certain intravenous preparations given in
large volumes as blood replenishers or as
nutrients are not permitted to contain
bacteriostatic additives, because the
amounts required to preserve such large
volumes would constitute a health hazard
when administered to the patient.





Examples of the preservatives and their
concentrations commonly employed in
pharmaceutical preparations are:
Benzoic acid (0.1 to 0.2%) （苯甲酸）
Sodium benzoate (0.1 to 0.2%)
Alcohol (15 to 20%)
Phenylmercuric nitrate and acetate (0.002 to
0.01%) （硝基苯汞和醋酸苯汞）
Phenol (0.1 to 0.5%) （苯酚）




Cresol (0.1 to 0.5%) （甲苯酚）
Chlorobutanol (0.5%) （氯丁醇）
Benzalkonium chloride (0.002 to 0.01%) （氯化苯
扎溴胺）
Combinations of methylparaben(尼泊金甲酯）
and propylparaben (0.1 to 0.2%) (尼泊金丙酯）,
this is especially good against fungas.
For each type of preparation to be preserved, the
research pharmacist must consider the influence
of the preservative on the comfort of the patient.
第六节
药物稳定性试验方法

本方法是参考国际协调会议文件与我国现
行药物稳定性试验指导原则和《美国药典》
23版有关文献制定的。

稳定性试验的目的：是考察原料药或药物
制剂在温度、湿度、光线的影响下随时间
变化的规律，为药品的生产、包装、贮存、
运输条件提供科学依据，同时通过试验建
立药品的有效期 。
稳定性试验的基本要求是：
① 稳定性试验包括影响因素试验、加速试验
与长期试验。影响因素试验适用原料药的
考察，用一批原料药进行。药物制剂影响
因素试验则在处方筛选与工艺研究中进行
加速试验与长期试验，适用于原料药与药
物制剂，要求用三批供试品进行；
②原料药供试品应是一定规模生产的，
供试验品量相当于制剂稳定性实验所
要求的批量，其合成工艺路线、方法、
步骤应与大生产一致。药物制剂的供
试品应是一定规模生产的，如片剂
（或胶囊剂）至少在1~2万片（或粒），
其处方与生产工艺应与大生产一致。
特殊剂型特殊品种所需数量根据具体
情况灵活掌握。
③供试品的质量标准应与各项基础研究及临
床验证所使用的供试品质量标准一致；
④加速试验与长期试验所用供试品的容器和
包装材料及包装应与上市产品一致；
⑤研究药物稳定性，要采用专属性强、准确、
精密、灵敏的药物分析方法与有关物质
（含降解产物和其他变化所生成的产物）
检查方法，并对方法进行确证，以保证药
物稳定性结果的可靠性。在稳定性试验中，
应重视有关物质的检查。
一、影响因素试验

影响因素试验（强化试验stress testing）
是在比加速试验更激烈的条件下进行。原
料药要求进行此项试验，其目的是探讨药
物的固有稳定性、了解影响其稳定性的因
素及可能的降解途径与降解产物，为制剂
生产工艺、包装、贮存条件与建立有关物
质分析方法提供科学依据。供试品可以用
一批原料药进行，将供试品置适宜的开口
容器中（如称量瓶或培养皿），摊成5mm
厚的薄层，疏松原料药摊成10mm厚薄层，
进行以下实验。
1. 高温试验

供试品开口置适宜的洁净容器中，60C温
度下放置十天，于第五、十天取样，按稳
定性重点考察项目进行检测，同时准确称
量试验前后供试品的重量，以考察供试品
风化失重的情况。若供试品有明显变化
（如含量下降5%）则在40C条件下同法进
行试验。若60C无明显变化，不再进行
40C试验。
2. 高湿度试验

供试品开口置恒湿密闭容器中，在25C分别于相
对湿度（905）%条件下放置十天，于第五、十
天取样，按稳定性重点考察项目要求检测，同时
准确称量试验前后供试品的重量，以考察供试品
的吸湿潮解性能。若吸湿增重5%以上，则在相对
湿度75%5%条件下，同法进行试验；若吸湿增重
5%以下且其他条件符合要求，则不再进行此项试
验。恒湿条件可在密闭容器如干燥器下部放置饱
和盐溶液，根据不同相对湿度的要求，可以选择
NaCl饱和溶液（相对湿度751%，15.5~60C），
KNO3饱和溶液（相对湿度92.5%, 25C）。
3. 强光照射试验

供试品开口放置在光橱或其它适宜的光照
仪器内，于照度为4500500Lx的条件下放
置十天（总照度量为120万Lx·h），于五、
十天取样，按稳定性重点考察项目进行检
测，特别要注意供试品的外观变化。有条
件时还应采用紫外光照射（200whr/m2）。
二、加速试验



加速试验(Accelerated testing)是在超常
的条件下进行。其目的是通过加速药物的化
学或物理变化，为药品审评、包装、运输及
贮存提供必要的资料。
原料药物与药物制剂均需进行此项试验，
供试品要求三批，按市售包装，在温度
402C，相对湿度755%的条件下放置六个
月。
所用设备应能控制温度 2C， 相对湿度
5%，并能对真实温度与湿度进行监测。

在试验期间每一个月取样一次，按稳定性
重点考察项目检测，3个月资料可用于新药
申报临床试验，6个月资料可用于申报生产。
在上述条件下，如六个月内供试品经检测
不符合制订的质量标准，则应在中间条件
下即在温度302C，相对湿度605%的情况
下（可用NaNO2饱和溶液，25~40C相对湿度
64%~61.5%）进行加速试验，时间仍为六个
月。

对温度特别敏感的药物制剂，预计只能在冰
箱（4~8C）内保存使用，此类药物制剂的
加速试验，可在温度252C，相对湿度
605%的条件下进行，时间为六个月。

乳剂、混悬剂、软膏剂、眼膏剂、栓剂、气
雾剂，泡腾片及泡腾颗粒宜直接采用温度
302C、相对湿度605%的条件进行试验，
其它要求与上述相同。

对于包装在半透性容器的药物制剂，如塑
料袋装溶液，塑料瓶装滴眼剂、滴鼻剂等，
则应在相对湿度202%的条件（可用
CH3COOK. 1.5H2O饱和溶液，25C，相对湿
度22.5%）进行试验。

光加速试验：其目的是为药物制剂包装贮
存条件提供依据。
三、长期试验




6个月的数据可用于新药
长期试验(Long-term testing)是在接近药品的
实际贮存条件25℃2℃下进行，其目的是为制
审批临床研究，12个月的
订药物的有效期提供依据。数据用于申报生产。
原料药与药物制剂均需进行长期试验，供试品
三批，市售包装，在温度252C，相对湿度
6010%的条件下放置12个月。每3个月取样一
次，分别于0、3、6、9、12个月，按稳定性重
点考察项目进行检测。
12个月以后，仍需继续考察，分别于18、24、
36个月取样进行检测。将结果与0月比较以确
定药品的有效期。
若未取得足够数据，应进行统计分析。

对温度特别敏感的药品，长期试验可在温度
62C的条件下放置12个月，按上述时间要求进
行检测，12个月以后，仍需按规定继续考察，制
订在低温贮存条件下的有效期。

此种方式确定的药品有效期，在药品标签及说明
书中均应指明在什么温度下保存，不得使用“室
温”之类的名词。

原料药进行加速试验与长期试验所用包装、应装
模拟小桶，但所用材料与封装条件应与大桶一致。
四、稳定性重点考查项目
剂型
稳定性重点考察项目
原料药
性状、熔点、含量、有色物质、吸湿性以及根据品种性质选定的考察
项目。
片 剂
性状、如为包衣片应同时考察片芯、含量、有关物质、崩解时限或溶
出度。
胶 囊
性状、内容物色泽、含量、有关物质、崩解时限或溶出度、水分，软
胶囊需要检查内容物有无沉淀。
注射液
外观色泽、含量、pH值、澄明度、有关物质。
栓 剂
性状、含量、软化、融变时限、有关物质。
软 膏
性状、含量、均匀性、粒度、有关物质，如乳膏还应检查有分层现象。
眼 膏
性状、含量、均匀性、粒度、有关物质。
滴眼剂
如为澄清液，应考察：
性状、澄明度、含量、pH值、有关物质、
如为混悬液，不检查澄明度、检查再悬浮性、颗粒细度。
丸剂
性状、含量、色泽、有关物质，溶散时限。
糖浆剂
性状、含量、澄清度、相对密度、有关物质、PH值
口 服 溶 液 性状 、含量、色泽、澄清度、有关物质。
剂
乳 剂
性状、含量、分层速度、有关物质。
混悬剂
性状、含量、再悬性、颗粒细度、有关物质。
酊 剂
性状、含量、有关物质、含醇量。
散 剂
性状、含量、粒度、外观均匀度、有关物质。
计 量 吸 入 容器严密性、含量、有关物质、每揿动一次的释放剂量，
气雾剂
有效部位药物沉积量。
膜 剂
性状、含量、溶化时限、有关物质。
颗粒剂
性状、含量、粒度、有关物质、溶化性。
透皮贴片
性状、含量、有关物质、释放度。
搽 剂
性状、含量、有关物质。
五、有效期统计分析


一般选择可以定量的指标进行处理，通常
根据药物含量变化计算，按照长期试验测
定数值，以标示量%对时间进行直线回归，
得回归方程，求出各时间点标示量的计算
值（y´），然后计算标示量（y´） 95%单侧
可信限的置信区间为y´±z 。
用时间与y、y´、y´+z、y´-z 作图，得图，
从标示量90%处划一条直线与置信区间下界
线相交，自交点作垂线于时间轴相交处，
即为有效期。
六、经典恒温法
-E/RT
K=Ae
 原理：
lgK=-E/2.303RT +lgA
lgC=-kt/2.303+lgC0

步骤：
1.预试验确定实验温度和取样时间
2.测定各温度各时间点药物的浓度
3.以同一温度的lgC对时间t作图，求出斜率，算
出各温度下的反应速率常数kT。
4.以k对（绝对）温度的倒数1/T作图，求出回归
方程。
5.将T=298代入回归方程，求出室温下的反应速
率常数 t0.9=0.1054/k，求得药物的有效期
举例： 每毫升含有800单位的某抗生素溶液，在25℃下放
置一个月其含量变为每毫升含600单位。若此抗生素的降解服
从一级反应，
问：（1）第40天时的含量为多少？（2）半衰期为多少？
（3）有效期为多少？
解： （1）求k：
由C =C0 e
K/RT
可知：K=（2.303／t）logC0/C
K=（2.303／30）log800/600=0.0096天1
0.0096=（2.303／40）log800/C
C =545单位
（2）求半衰期：
t
1/2＝0.693/0.0096
= 72.7天
（3）求有效期：
t
0.9＝0.1054/0.0096
= 11天