Transcript preformulation_and_formulation(보충자료)
PHARMACEUTICAL PREFORMULATION AND FORMULATION
- Preformulation Investigations using Small Amounts of Compound as an Aid to Candidate Drug Selection and Early Development
Introduction: Decision gate system
Introduction: New drug R&D process
Introduction
• Increasing in pressure on pharmaceutical companies to discover and develop new medicines ever faster to replace those coming off patent and to counter generic manufacturer competition.
• Since 1990 an average of only 28 drugs have been approved each year. • Approved only 17 new chemical entities (NCEs) in 2002 (the lowest approvals).
• Success rate of bringing a candidate drug (CD) to market is no more than 10%.
• Out of 30,000 compounds synthesized only 0.003% of discovery compounds will show a satisfactory return on investment.
One idea to increase the productivity of the drug discovery process is to eliminate those steps in the process that do not add value to the process chain.
• • • Drug discovery process: lead generation (LG), lead optimization (LO) LG period: subdivided into the active to-hit(AtH) and the hit-to-lead (HtL) phases.
HtL phase: - utilizes high-throughput screening (HTS) and generates actives, hits, and leads.
- increases the drug-like properties (e.g., improve potency, selectivity, pharmacokinetic properties, and decrease toxicity)
Introduction
• Leads: compounds that meet predefined chemical and biological criteria, drug-like properties.
• LO phase (=prenomination) - Structure-activity relationships (SARs), which correlate molecular properties with biological effects, are derived.
- Iterative assessment of optimized leads --> identification of the most promising lead candidates.
- 3~6 months - Investigations for the physicochemical characterization of the solid and solution properties of CD compounds.
- The aim of this phase: To provide an initial evaluation of compounds from a development perspective and support the tolerability studies of compounds.
- During prenomination, compounds need to be evaluated in animals for exposure/toxicity purposes [7-day tox and 28-day single and multiple ascending doses].
Introduction
- During the prenomination phase, 50 to 100 mg compound is typically available.
- A poor decision at this point revisionary work e.g., change of salt or polymorph delay to the development of the drug for the market • If the compound progresses into full development, a more complete physicochemical characterization of the chosen compound should be carried out.
Allowing a rational, stable, and bioavailable formulation to be progressed through to launch.
• The biggest change in the last decade.: Utilization of HTS technologies. Large number of compounds can be assessed for efficient physicochemical profiling, as well as salt and polymorph screening.
Introduction
Introduction
Introduction
MOLECULAR PROPERTIES
Initial Physicochemical Characterization
• • Initial physicochemical characterization: 2-dimensional structural properties • Performed by the discovery department.
• For example Nuclear magnetic resonance (NMR), mass spectra analysis, and elemental analysis.
This text will focus on those tests carried out during prenomination that will have an important bearing on the selection of a potential CD
pKa Determinations
• • • • Potential CDs that possess ionizable groups can be exploited to vary biological and physical properties (e.g., binding to target enzyme or receptor, binding to plasma proteins, gastrointestinal (GI) absorption, central nervous system (CNS) penetration, solubility, and rate of dissolution).
Therefore, one of the most important initial determinations carried out prior to their development is the pKa or ionization constant(s).
It is essential to know the extent to which the molecule is ionized at a certain pH, because it affects the properties noted above.
• Brønstead and Lowry theory of acids and bases: An acid is a substance that can donate a hydrogen ion, and a base is one that can accept a proton. For a weak acid, the following equilibrium holds: • Henderson–Hasselbach equation relates the pKa to the pH of the solution and the relative concentrations of the dissociated and undissociated parts of a weak acid (equation 1).
pKa Determinations
• Equation (2) to yield the percentage of a compound that will be ionized at any particular pH.
•
Measurement of pKa
pKa Determinations
1) If a compound is poorly soluble in water Measure the apparent pKa of the compound in solvent-water mixtures, and then extrapolate the data back to a purely aqueous medium (Methanol is by far the most popular).
2) If the compound contains an ultraviolet (UV) chromophore UV spectroscopy can be used. Mathematical analysis of the spectral shifts can then be used to determine the pKa(s) of the compound.
3) pH indicator titration A novel approach The method works by calculating the pH from the indicator spectra in the visible region and then obtaining the spectra in the UV 4) High-throughput pKa measurements The determinations were conducted in 96-well plates using 10-mM DMSO solutions Determination of the pKa is via the change in UV absorbance at multiple wavelengths as a function of pH.
pKa Determinations
The Sirius ProfilerSGA (spectral gradient analysis) instrument: - To deal with the ever-increasing numbers of compounds - For high-throughput applications - To overcome the low solubility exhibited by modern CDs, pKa measurements are carried out in, for example, methanol-water mixtures.
- To overcome extreme solubility limitations of some compounds, a ternary solvent system (methanol : dioxane : acetonitrile = 1:1:1) has been developed. •
Prediction of pKa
The pKa may be estimated using a number of software packages, for example, PALLAS, MARVIN, ACDpKa, and SPARC
The Partition and Distribution Coefficients
• • Many biological phenomena can be correlated with the partition coefficient (log P) • Solubility, absorption potential, membrane permeability, plasma protein binding, volume of distribution, and renal and hepatic clearance.
log P can be defined as the ratio of the concentration of the unionized compound, at equilibrium, between organic and aqueous phases (equation 3).
• • • • • log P = 0 means that the compound is equally soluble in water and the partitioning solvent. If the compound has a log P = 5, then the compound is 100,000 times more soluble in the partitioning solvent.
log P values of less than 5 are best from a drug-like perspective. log P values 1~ 3 show good absorption, greater than 6 or less than 3 often have poor transport characteristics. Highly lipophilic molecules reside in the lipophilic regions of membranes, and very polar compounds show poor bioavailability because of their inability to penetrate membrane barriers.
The Partition and Distribution Coefficients
• Distribution coefficient (log D) takes into account the dissociation of weak acids and bases. For a weak acid this is defined by equation (4).
• • combining this equation with equation (1) gives an expression relating the distribution to the intrinsic lipophilicity (log P), the pKa of the molecule, and the pH of the aqueous phase (equation 5).
Figure 1 shows the effect of ionization on the partitioning of a proton pump inhibitor compound. This compound has a log P of 3.82 and three pKa values, that is, 1, 5.26, and 8.63.
INITIAL SOLUBILITY INVESTIGATIONS
INITIAL SOLUBILITY INVESTIGATIONS
• • • • The solubility of a CD may be the critical factor determining its usefulness since aqueous solubility dictates the amount of compound that will dissolve and, therefore, the amount available for absorption.
The importance of solubility, in biopharmaceutical terms, has been highlighted by its use in the biopharmaceutics classification system (BCS).
High solubility is defined as the highest dose strength that is soluble in 250 mL.
Poorly soluble drugs: defined as an aqueous solubility of less than 100 mg/mL From a physicochemical perspective, James (1986) has provided some general rules regarding solubility: 1. Electrolytes dissolve in conducting solvents.
2. Solutes containing hydrogen capable of forming hydrogen bonds (H-bonds) dissolve in solvents capable of accepting H-bonds and vice versa.
3. Solutes having significant dipole moments dissolve in solvents having significant dipole moments.
4. Solutes with low or zero dipole moments dissolve in solvents with low or zero dipole moments
INITIAL SOLUBILITY INVESTIGATIONS
• The United States Pharmacopeia (USP) (Table 3) gives the following definitions of solubility.
Phase Solubility Analysis
• • • • To more accurately determine the concentration of a saturated solution of a compound, the following procedure can be used. - A known volume of the solvent, water or buffer, is pipetted into a vial.
- The compound of interest is added until saturation is observed to occur.
- If the compound dissolves, then more compound is added and the experiment restarted.
For HTS of solubilities, 96-well microtiter technique with an integral nephelometer could be used.
Because of the differences in melting point and other characteristics of polymorphs, solubility differences are often observed. Usually the most stable form of the compound has the lowest solubility in any solvent.
Many CDs are ionizable organic compounds, and thus there are a number of parameters that will determine the solubility of a compound, for example, molecular size and substituent groups on the molecule, degree of ionization, ionic strength, salt form, temperature, crystal properties, and complexation.
Phase Solubility Analysis
• • • • To more accurately determine the concentration of a saturated solution of a compound, the following procedure can be used. - A known volume of the solvent, water or buffer, is pipetted into a vial.
- The compound of interest is added until saturation is observed to occur.
- If the compound dissolves, then more compound is added and the experiment restarted.
For HTS of solubilities, 96-well microtiter technique with an integral nephelometer could be used.
Because of the differences in melting point and other characteristics of polymorphs, solubility differences are often observed. Usually the most stable form of the compound has the lowest solubility in any solvent.
Many CDs are ionizable organic compounds, and thus there are a number of parameters that will determine the solubility of a compound, for example, molecular size and substituent groups on the molecule, degree of ionization, ionic strength, salt form, temperature, crystal properties, and complexation.
Effect of Molecular Size on Solubility
• • • Because of interactions between the nonpolar groups and water, Large organic molecules have a smaller aqueous solubility than smaller molecules.
It is dependent on the number of solvent molecules that can pack around the solute molecule.
Figure 2 shows the effect of molecular weight on the solubility of some amino acids in water.
INITIAL STABILITY INVESTIGATIONS
INITIAL STABILITY INVESTIGATIONS
• • • • • • Knowledge about the chemical and physical stability of a CD in the solid and liquid state is extremely important in drug development.
In the longer term, the stability of the formulation will dictate the shelf life of the marketed product.
ICH spec.: The allowable levels of a single impurity permissible without toxicological cover is much less than 1%.
To elucidate their stability with respect to, for example, temperature, pH, light, and oxygen, a number of experiments need to be performed. The major objectives of preformulation team are therefore to (1) identify conditions to which the compound is sensitive and (2) identify degradation profiles under these conditions.
The main routes of drug degradation in solution are via hydrolysis, oxidation, or photochemical means.
Solution Stability
• • • • • • • Hydrolysis Degradation by hydrolysis is affected by a number of factors, of which solution pH, buffer salts, and ionic strength are the most important. In addition, the presence of cosolvents, complexing agents, and surfactants can also affect this type of degradation.
As noted, solution pH is one of major determinants of the stability of a compound.
Hydroxyl ions are stronger nucleophiles than water, thus degradation reactions are usually faster in alkaline solutions than in water, that is, OH– ions catalyze the reaction. In solutions of low pH, H + can also catalyze hydrolysis reactions.
Buffer ions such as acetate or citrate can catalyze degradation.
Table 5 shows some examples of the functional groups that undergo hydrolysis.
Solution Stability
• Therefore, although it is prudent to adjust the pH to the desired value to optimize stability, this should always be done with the minimum concentration necessary.
• • • Oxidation The second most common way a compound can decompose in solution is via oxidation. Reduction/oxidation (redox) reactions involve one of the following processes: (1) transfer of oxygen or hydrogen atoms or (2) transfer of electrons. Oxidation is promoted by the presence of oxygen, and the reaction can be initiated by the action of heat, light, or trace metal ions that produce organic free radicals.
THE ORGANIC SOLID STATE
THE ORGANIC SOLID STATE
• • • • • • • Molecular solids can exist as crystalline or noncrystalline (amorphous) phases depending on the extent of three-dimensional order and the relative thermodynamic stability hierarchy.
Crystalline states can be described as a periodic array of molecules within a three dimensional framework.
Noncrystalline materials lack significant three-dimensional order, but may exhibit lower-dimensional short-range order.
“Crystal proper” is defined as one in which the molecule is repeated to 10,000 to 100,000 times.
The structures of molecular crystals are influenced by both intramolecular and intermolecular interactions.
Intramolecular forces determine molecular shape.
Intermolecular forces are relatively weak, their effect is largely short range.
diversity in the arrangement of molecules within the molecular crystals is brought about, which also gives rise to differences in properties and performance of the molecular crystals.
Crystalline States and Structural Assessment
Polymorphism and Related Phenomena • • • • • Polymorphism is a solid-state phenomenon where the crystal structures of a chemical entity are different, but correspond to identical liquid and vapor states.
A variation in crystal structure is brought about by differences in molecular packing and intermolecular interactions within the three-dimensional framework of the crystalline state.
Polymorphs will have different lattice energies, which in turn govern the physical properties and behaviors of the material.
Specifically, in the area of pharmaceutical material selection, polymorphs are selected on the basis of physical and chemical stability, behavior to processing and formulation, and biopharmaceutical properties as an assessment of in vivo performance.
Other differences in properties also include thermodynamic and kinetic variations between polymorphs.
Crystalline States and Structural Assessment
Polymorphism and Related Phenomena • • In addition to simple variations in hydrogen bonding, polymorphism can also be induced by conformational differences, that is, the existence of different conformers of the same molecule in different polymorphic modifications. different solubility properties.
Conformational polymorphism different solubility properties diversity in bulk properties: e.g., polychromism, different color, red, yellow, and orange directly due to a variation in the molecular conformation, giving rise to different three-dimensional packing
Polymorph Production Methods
• Both solvent-mediated and nonsolvent-induced polymorphism can be employed.
1. Crystallization from different solvents under variable conditions, for example, different agitation speeds and temperatures. 2. Precipitation by, for example, addition of an antisolvent to a solution containing the drug or by pH adjustment of solutions of weak acids or bases. (e.g., quasi-emulsion precipitation of a number of polymorphic compounds using PEG300 as the solvent and water as the antisolvent.
3. Concentration or evaporation.
4. Formation of polymorphs from solvate desolvation. E.g., forms I of spironolactone could be obtained by desolvation of its ethanol solvate.
Polymorph Production Methods
5. Crystallization from the melt, assuming that melting is not accompanied by thermal degradation.
6. Grinding and compression.
7. Lyophilization (freeze-drying) 8. Spray-drying. Amorphous ursodeoxycholic acid can be prepared by spray-drying.
9. Crystallization from supercritical fluids.
10. Potentiometric cycling.
11. High pressure.
12. Sublimation. Exploiting the vapor phase as a solvent-free method
Case study : The Items for DGS (Decision gate system)
Preformulation, formulation study in R&D stage
Test Items Physicochemical characterization Salt selection pH-Solubility pH-Stability Solid stability (Stability test) Hygroscopicity Intrinsic dissolution rate (IDR) Structure determination (XRD) Preclinical formulation Particle size analysis Excipient compatibility Polymorphism study Phase I formulation (Formulated capsule) Clinical formulation (Tablet or capsule) Stage
연구
/
전임상단계 연구
/
전임상단계 연구
/
전임상단계 연구
/
전임상단계 연구
/
전임상단계 전임상단계 전임상단계 전임상단계 전임상단계 전임상
/
임상단계 전임상
/
임상단계 전임상
/
임상단계 임상단계 임상단계
Remarks
Principal areas of preformulation research
Ⅰ. Bulk Characterization Crystallinity and Polymorphism Hygroscopicity Fine Particle Characterization Bulk Density Powder Flow Properties Ⅱ. Solubility Analysis Ionization Constant-pKa pH Solubility Profile Thermal Effects Solubilization Partition Coefficient Dissolution Ⅲ. Stability Analysis Stability in Toxicology Formulations Solution Stability pH Rate Profile Solid State Stability Bulk Stability Compatibility
Preformulation research - Lead optimization stage
Physicochemical Characterization 시험구분 중요성 연구단계
&
전임상 단계 시험 항목 필요시료량 소요기간
100mg 1
주
- Lead
화합물이나 전임상후보 화합물의 물리화학적 특성을
1
차적으로 측정함
.
-
물리적 특성에 따라
salt
또는
polymorph
의 개발 여부를 판단하며
, lead
최적화 단계에서는 구조 변형의 여부 판단에 관여됨
.
시험방법
Criteria
용어설명
-
구조분석
: NMR, IR, UV/VIS, MASS, XRD -
열분석
: DSC, TGA-MASS, HSM - pKa, LogP/LogD - Log P
가
> 5
용해도가 낮아 개발이 어려움
Salt
화 가능성 판단
- Log P
가
< 0
흡수가 어려움
Prodrug
가능성 판단
- XRD (X-ray diffraction): X-
선을 이용한 결정 격자 회절 방법
,
결정의 구조를 조사
- DSC (Differential scanning calorimetry): API
의 온도변화에 따른 열량 변화를 관찰
,
일반적으로 화합물의
Melting temperature
를 결정하는 데 사용
- TGA (Thermogravimetric analysis)-MASS: API
의 온도에 따른 질량변화를 관찰
.
주로
hydrate
나
solvate
생성 여부를 관찰
- HSM: Hot-stage microscopy
온도 변화에 따른 결정의 변화를 현미경으로 관찰
Salt Selection 시험구분 중요성 연구단계
&
전임상 단계 시험 항목 필요시료량 소요기간
300mg 2~4
개월
-
전임상 후보에 대한 적합한
salt
형을 선정함
-
난용성
API
인 경우
salt
를 만들어
solubility
를 증대시킴
- Free form
이 비정질이어서 안정성이 떨어지는 경우
salt
로 만들어
stability
를 증대시킴
.
-
흡습성이 큰
API
의 경우 적절한
salt
형으로 만들어 문제를 제거함 시험방법
- API
에
basic
한 작용기
(
주로
amine)
가 있는 경우
acid
를 반응시켜 물에 잘 녹는
salt
를 만듦
.
- Salt
의 용해도와 생성여부를 판단하기 위해 먼저
in situ salt screening
을 실시함
.
Criteria
용어설명
- Solubility - Stability - Crystallinity (Crystal Shape) -
비정질
(amorphous):
결정성
(crystallinity)
이 없거나 매우 작은
solid form
으로 일반적으로는
solubility
가 증가하지만
stability
는 떨어짐
.
pH-Solubility 시험구분 중요성 연구단계
&
전임상 단계 시험 항목 필요시료량 소요기간
100mg 1
주
- API
의 수용액상
Solubility
는 약물의 생체 흡수와 관련이 있어 약물의 유용성 면에서 매우 중요함
.
-
각 장기 마다
pH
가 다르기 때문에
pH
에 따른 화합물의
solubility
는 궁극적으로 약물 흡수와 관련이 있음
.
시험방법
-
여러 다른
pH
완충수용액을 만들어 일정량의
API
를 넣어
37
℃ 로 유지시킨 다음 수용액상
API
의 농도를
HPLC
를 이용하여 분석함
.
Criteria -
주사제
: 30mg/mL
이상이면 이상적
,
투여 용량에 따라 달라짐
-
경구제
: Dose/250mL
이상이면 이상적
(
예
, 250mg
을 투여해야 하는 경우
>1mg/mL)
용어설명
pH-Stability 시험구분 중요성 연구단계
&
전임상 단계 시험 항목 필요시료량 소요기간
100mg 1
주
- API
의 수용액상
Stability
는 약물의 흡수 전후의
degradation
이나
chemical conversion*
등을 관찰하거나 예견하는데 유용함
.
- API
가 가장
stable
한
pH
조건을 찾아내어
solution
상태의
formulation
개발에 활용할 수 있음
(
동물실험 제형 및 사람에서의
solution
제형에 이용 가능
)
시험방법
-
여러 다른
pH
완충수용액을 만들어 일정량의
API
를 넣어
37
℃ 로 유지시킨 다음 수용액상
API
의 농도를
HPLC
를 이용하여 분석함
.
Criteria
용어설명
- 24
시간 경과 후에도
95%
이상 유지
- Chemical conversion:
효소의 관여 없이 이화학적인 조건에서 화합물의
configuration
이 변화하는 것
(Cis-trans conversion)
Solid Stability 시험구분 중요성 연구단계
&
전임상 단계 시험 항목 필요시료량 소요기간
100mg 4
주
- API
의 열에 대한
stability
를 조사함
.
-
빠른 판단을 위하여
stressed condition (60
℃
)
에서
4
주간
stability
를 조사함
.
-
개발후보로 선정된 경우는
ICH guideline
에 따라 분석팀에서 실시함
.
시험방법
-
시료를
60
℃ 항온
chamber
에 보관하며
, 1
주일 간격으로
sampling
하여
HPLC
로 남아있는 시료량의 순도
*
를 분석함
.
Criteria
용어설명
-
가혹조건
(60
℃
)
에서
3
주 경과 후
95%
이상
, 4
주 경과 후
90%
이상 순도가 유지되는 경우
stable -
순도
(Purity):
일반적으로 순도는
HPLC
를 이용하여
main peak
의
% peak area
를 계산하여 결정함
.
Preformulation/Formulation research - Preclinical stage
Hygroscopicity 시험구분 중요성 전임상 단계 시험 항목 필요시료량 소요기간
500mg 2
주
- API
는 흡습성 정도에 따라 본래의 결정형을 유지하는 조건 및 시간이 정해짐
.
- Highly hygroscopic
하거나
moderately hygroscopic
한 경우
moisture
를 효과적으로 막을 수 있는 방법을 반드시 모색하여야 함
.
시험방법
Criteria - API
를 각각 상대습도가 다르게 정해진 용기에 넣고 용기 들을 온도가 조절되는 항온 장치에 보관하여 수일 간격으로 보관된
API
의 무게 변화를 측정함
.
-
무게 변화는
API
에 수분의 변화를 설명하여
,
이 경우 가시적으로 수분에 의한
API
의 용해를 관찰할 수 있음
.
- Hydrate
형성 유무
, non-or slightly hygroscopic
용어설명
- Hydrate:
화합물에 물이 일정한 비율로 포함되어 있는 것
.
Intrinsic Dissolution Rate (IDR) 시험구분 중요성 전임상 단계 시험 항목 필요시료량 소요기간
100mg 2
일
- API
가 수용액에서의 용출되는 속도를 나타냄
.
-
결정형
(polymorph)
이나
salt
의 종류에 따라서도 다르며
,
약물의 제형화에 직접적으로 관련됨
.
- IDR
결과를 비교하여 우수한 결정형이나
salt
를 선정함
.
시험방법
- API
로 원형의
pellet
을 만들어
pH
에 따른 용출 속도를 측정함
.
Criteria - pH
에 따른 용출속도
(
기울기가 클수록 용출이 좋음
).
여러
API
의 비교 시
rate
로 비교
. -
경구 제형의
dissolution
과 연관하여
pH1.2
에서
1
시간 이내에
90%
이상 용출되는 것이 바람직함
.
용어설명
Structure Determination (XRD) 시험구분 전임상 단계 시험 항목 필요시료량 소요기간
1g 1~2
개월 중요성
- API
의 결정구조 결정에 의해 개발 물질의 분자구조를 검증하고
final form
을 확정함
.
시험방법
Criteria - API
를 여러 가지 결정화 조건에 따라 적당한 크기의 단결정을 키운다
.
-
단결정을 이용하여
single-crystal diffractometer
에서 격자회절을 측정한 다음
software
를 이용
,
결정구조를 결정하고 정밀화함
.
- R1 value 10%
이하
(%
는 실측된 구조와 모델 구조와의 차이로 작은 수치가 좋다
.) - R2 value 30%
이하
(R1
과
R2
는 구조 정밀화 후 자동으로 산출됨
)
용어설명
Preclinical Formulation 시험구분 중요성 전임상 단계 시험 항목 필요시료량 소요기간
20~30mg 2
주
-
전임상 시험에서는 주로
solution formulation
을 이용하는데
, API
를 필요한 농도에서
clear
하게 녹일 수 있는
vehicle
을 찾아내어
PK, Pre-toxicology, Toxicology study
등에 사용하고자 함
.
시험방법
Criteria - API
를 필요한 농도에서
clear
하게 녹이는 최적의
formulation
을 찾아냄
.
- Formulation
은 동물에 적용 가능한
vehicle
을 사용해야 하며
,
해당
formulation
에 대한
formulation stability
를
1~2
주간 측정한 후 확정함
.
-
원하는 용해도와
stability
를 만족하는 경우 용어설명
Particle Size Analysis 시험구분 중요성 전임상 단계
&
임상 단계 시험 항목 필요시료량 소요기간
200mg 1
주
- Particle size
에 따라
Tablet
의 성형 정도 또는
Capsule
에 충전 정도에 영향을 미치기 때문에
API
의
Particle size
는 약물의 제형화에 필수적 요소임
.
시험방법
Criteria
용어설명
- API
를 적당한
medium
에 분산시켜
Light scattering particle size analyzer
로 측정
-
또는 현미경 하에서 디지털 카메라로 찍어
software
로 화면상의
particle size
를 측정함
.
- Size (Uniformity), Shape (Uniformity,
선호도
Prismatic > Plate, Needle)
등 결과를 종합하여
Processability
판단에 반영
.
-
제제시험 후 최적
particle size distribution
선정
- Light scattering: laser
빛이 용액 내
particle
에 부딪혀
scattering
됨을 이용하여
particle
의
size distribution
을 측정함
.
Excipient Compatibility 시험구분 중요성 전임상 단계
&
임상 단계 시험 항목 필요시료량 소요기간
10~20g 2~6
개월
-
임상 개발후보의 제제화 시
Capsule
이나
Tablet
제형에 들어갈 여러 가지 기능의 부형제 및 첨가제와 약물의 상호작용을 조사하여
compatible
한 부형제 및 첨가제를 선정하고자 함
.
시험방법
Criteria - API
와 각각의 부형제를
1:1
로 혼합하거나 여러 가지 부형제를 동시에 혼합하여
stressed condition (50
℃ 또는
60
℃
)
에 보관한 후
1
개월 간격으로 상호작용을
DSC/TGA, XRD
와
HPLC
등으로 분석을 하여
, API
와 가장
compatible
한
excipient
를 선정함
.
-
새로운
peak
생성여부
(50
℃ 에
1
개월 보관 후 새로운
peak
를 생성하지 않거나
3
개월 이내에 새로운
peak
의 비율이
5%
이내의
excipient
를 선정한다
.
-
또는
60
℃ 에
1
개월 보관 후 새로운
peak
를 생성하지 않거나 생성된
peak
의 비율이
5%
이내의
excipient
를 선정한다
.
용어설명
Polymorphism Study 시험구분 중요성 시험방법
Criteria
용어설명 전임상 단계
&
임상 단계 시험 항목 필요시료량 소요기간
50g 6
개월
~1
년
- API
의
polymorph*
를 조사하여 그 중 가장 적합한 것을 선정하여
final form
으로 결정함
.
-
전임상 단계에서
Salt
인 경우와 아닌 경우에서 가능한
polymorph
를 제조 및 물성 분석을 통하여
Final form
으로 선정하고 개발 후보를 선정함
.
- API
를 다양한 용매와 결정화 조건을 통하여 여러 가지 다른 결정형을 찾아냄
.
-
각 결정형들의
Solubility, Stability, IDR*
등 물성을 비교
-
각 결정형들 사이에 변화
(transformation)
가 있는지 조사
-
임상샘플 제조 시
polymorph
의 생성 또는 변형을 조사
-
초기
screening
에
50mg
이 소요되며
, polymorph
가 발견되면 추가 실험에
50g
필요
- Solubility, Stability, IDR - Polymorph:
동일한 화합물이 여러 가지 결정형을 가지는 경우 결정형에 따라 물리적 성질이 달라 약효도 달라질 수 있음
.
- IDR (Intrinsic dissolution rate):
화합물이 수용액 용출되는 정도를 나타내는 수치
Bioavailability
와 관련됨
.
Phase I Formulation (Formulated Capsule) 시험구분 중요성 임상 단계 시험 항목 필요시료량 소요기간
100g 3~6
개월
-
임상
1
상 시험에 적합한 제형을 선정함
.
-
체내에 투여되는
form
이기 때문에 일반 의약품과 유사한 제형 형태로 만들어야 하며
,
균일한 함량과 임상시험 실시 기간까지의 샘플의
stability
확보가 중요한
factor
임
.
시험방법
Criteria -
임상시험에 사용할 용량의 약물을
excipient compatible test
에서 선정된 부형제와 혼합하여
capsule
에 충전한 후
, stability test
를 진행하여 가장 적합한
formulation
을 선정함
.
-
함량균일성
,
용출
, Stability
용어설명
-
함량균일성
(Content uniformity):
약물이 제형에 균일하게 잘 섞여있는 정도
.
특히 약물 용량이 적은 경우
critical
함
.
Clinical Formulation (Tablet or Capsule) 시험구분 중요성 임상 단계 시험 항목 필요시료량 소요기간
1kg 1~3
년
-
임상
2,3
상 시험에 적합한 제형을 선정함
.
- Clinical formulation
은 약효시험 등 장기적인 시험에 이용되고 또
commercial production
의 기초가 되는 제형임
.
시험방법
Criteria - API
의
Excipient compatibility test
를 통하여 선정된 부형제를 이용하여 적합한 크기의
Tablet
이나
Capsule
을 제조하여 함량균일성과 용출 및
Stability
를 관찰하여 최적화된 제형을 선정함
.
-
함량균일성
,
용출
, Stability
용어설명