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Solid State Pharmaceutical.ppt
1. The physicochemical properties of active pharmaceutical
ingredients are key factors to the development of
appropriate dosage forms.
Most organic substances exist in solid state :
1. Polymorphs
2. Amorphous forms
3. Pseudo-polymorphs (solvates)
Solid state pharmaceutical
2.
3. Crystals comprise a rigid lattice of molecules, atoms, or
ions. The regularity of the internal structure of this solid
body results in the crystal having characteristic shape.
Four types of crystalline solid may be specified: ionic,
covalent, molecular, and metallic.
4. Ionic crystals (e.g., sodium chloride) consist of charged ions held in
place in the lattice by electrostatic forces. Each ion is separated from
oppositely charged ions by regions of negligible electron density.
Covalent crystals (e.g., diamond) consist of constituent atoms, which
do not carry effective charges. A framework of covalent bonds, through
which their outer electrons are shared, connects these atoms.
Molecular crystals (e.g., organic compounds) are discrete molecules
held together by weak attractive forces (pi-bonds, hydrogenbonds).
Metallic crystals (e.g., copper) comprise ordered arrays of identical
cations. The constituent atoms share their outer electrons, which are
free to move through the crystal and confer “metallic” properties on the
solid.
Solid State Bonding
5. Polymorphism :
the ability of a substance to exist as two or more
crystalline phases that have different arrangements
and/or conformations of the molecules in the
crystal lattice.
In the solid state, the atoms, molecules or ions may
be arranged in one of the fundamental crystal
systems:
Triclinic, monoclinic, orthorhombic, tetragonal,
trigonal, hexagonal or cubic
7. The most widely known example of polymorphism is the
element carbon, which can exist in the form of graphite
(hexagonal) and diamond (cubic).
The polymorphic solids have different unit cells and hence
display different physical properties, including those due to
packing, and various thermodynamic, spectroscopic,
interfacial, and mechanical properties.
8. Acetaminophen bisa eksis
sebagai monoklinik (b)
bentuk yang
termodinamika stabil di
bawah kondisi ruangan
dan sebagai ortorombik
kurang stabil (a) bentuk,
memiliki kepadatan yang
lebih tinggi menunjukkan
kemasan lebih dekat.
9. Di sisi lain, spiperone ini molekul
berisi rantai fleksibel-CH2-CH2-
CH2- dan karena itu mampu
yang ada di konformasi molekul
yang berbeda, menimbulkan dua
polimorf konformasi yang
berbeda (dilambangkan Formulir
I dan II), yang memiliki sel satuan
yang berbeda dan kepadatan
10. 1. Packing properties
a. Molar volume and density
b. Refractive index
c. Conductivity, electrical and thermal
d. Hygroscopicity
2. Thermodynamic properties
a. Melting and sublimation temperatures
b. Internal energy (i.e., Structural energy)
c. Enthalpy (i.e., Heat content)
d. Heat capacity
e. Entropy
f. Free energy and chemical potential
g. Thermodynamic activity
h. Vapor pressure
i. Solubility
Physical Properties that Differ Among Various Polymorphs
11. 3. Spectroscopic properties
a. Electronic transitions (i.e., ultraviolet-visible absorption spectra)
b. Vibrational transitions (i.e., infrared absorption spectra and Raman
spectra)
c. Rotational transitions (i.e., far infrared or microwave absorption
spectra)
d. Nuclear spin transitions (i.e., nuclear magnetic resonance spectra)
4. Kinetic properties
a. Dissolution rate
b. Rates of solid state reactions
c. Stability
5. Surface properties
a. Surface free energy
b. Interfacial tensions
c. Habit (i.e., shape)
6. Mechanical properties
a. Hardness
b. Tensile strength
c. Compactibility, tableting
d. Handling, flow, and blending
12. Many pharmaceutical solids can exist in an amorphous form, which,
because of its distinctive properties, is sometimes regarded as a
polymorph. However, unlike true polymorphs, amorphous forms are
not crystalline.
Sifat amorf
amorphous solids consist of disordered arrangements of molecules
and therefore possess no distinguishable crystal lattice nor unit cell
and consequently have zero crystallinity
13. Diagram skematik yang
menunjukkan perbedaan dalam
rangka jangka panjang dari silikon
dioksida dalam (a) negara kristal
(crystobalite) dan (b) keadaan
amorf (gelas silika).
14. The name “glassy state” is given to amorphous products which
change from glassy state to rubber state by undergoing a glass
transition.
Thermodynamically, the absence of stabilizing lattice
energy causes the molar internal energy or molar enthalpy
of the amorphous form to exceed that of the crystalline
state
High Energetic Forms
15. Chemical reactivity of Amorphous Solid
The amorphous state is very reactive
Examples of stability behaviours of crystalline and amorphous forms
Example 1. Degradation after 1 month stress at 80°C under
oxygen or moisture
Crystalline form A no degradation
Crystalline form B 0.5.1.5% degradation
Amorphous form 2.3.5% degradation
Example 2. Degradation after 1 week at 70°C
Crystalline form 10% degradation
Amorphous form 80% degradation
Example 2. Degradation after light exposure, 300 kluxh
Crystalline form 2% degradation
Amorphous form 38% degradation
16. A B
A) SEM Amorphous Forms and B) one crystalline form
17. on the polymorphism of chloramphenicol palmitate followed
Anderson’s investigation of the unsatisfactory therapeutic effect of a
suspension of that drug. In this case, the bioavailability of the stable
polymorph (form A) was found to be inadequate, whereas the
bioavailability of the metastable polymorph (form B) was satisfactory
for pharmacotherapy.
19. Carbamazepine, a pharmaceutical used in the treatment of
epilepsy and trigeminal neuralgia, is a tetramorphic system
possessing nearly identical molecular conformation and
strong hydrogen bonding among its polymorphs.
20. Awell-known example of this is the Norvir® brand of ritonavir
semisolid capsules . Commercial start-up began in January
1996. During 1998 the drug began to precipitate in the
capsules. These precipitations in the capsules lead to
dissolution failures for the semisolid capsule. The Form I
polymorph, which was initially used in the semisolid
capsules, converted to a less soluble Form II.This change in
polymorphic form during stability caused a great deal of
market disturbance for this product.
21. The process of transformation of one polymorph into
another is a phase transition, may occur at a given
pressure by changing the temperature.
If the phase transition is reversible, the two polymorphs
are enantiotropes.
If the phase transition is irreversible, the two
polymorphs are monotropes, in which case only one
form is stable whatever the temperature.
22. Unstable Forms Stable Forms
phase transition
Transition Point
1. TERMODINAMIC : The Changes in various condition function
2. KINETIC : The rate of transformation
24. larutan
polimorf sejati solvat
leburan
padatan amorf
(kaca)
desolvat
isomerik
KR KR
FD
SD
PR
DE,SC,WG
KR
KR
ME
HE
QC
MI,WG,
SDSP
DE
DE ESV
Jenis polimorf yang dapat dihasilkan melalui proses baku farmasi. Kristalisasi (KR),
desolvasi (DE), kontak dengan uap pelarut (ESV), freeze drying (FD), pemanasan (HE),
melebur (ME), milling (MI), presipitasi (PR), quench cooling (QC), slurry conversion
(SC), spray drying (SD), solid dispersion (SDSP), granulasi basah (WG)
25.
26. Scan 1. The sample studied is the stable form A, which gives the
endothermic solid phase transition A B followed by the melting
endotherm of form B.
Scan 2. The sample studied is the stable form A, but for kinetic
reasons, e. g.a too fast heating rate, the solid transformation A B
does not occur. Instead, form A melts.
Scan 3. The sample studied is the stable form A which melts. Form B
grows from the melt with an exothermic peak and form B melts at a
higher temperature.
Scan 4. The sample studied is the metastable form B, which becomes
stable at a higher temperature above the transition temperature. An
exothermic peak corresponds to the solid transformation B A
followed by successive transformation A B and melting of B.
Scan 5. The sample studied is the metastable form B. The DSC scan
shows its melting endotherm.
Case of Enantiotropy
27. Examples showing such behavior (enantiotropic) include
acetazolamide, carbamazepine, metochlopramide, and
tolbutamide.
Sometimes only one polymorph is stable at all temperatures below
the melting point, with all other polymorphs being therefore unstable.
These polymorphs are said to be monotropes, and the system of the
two solid phases is said to be monotropic.
Examples of this type of system include chloramphenicol
palmitate and metolazone
29. Case of Monotropy
Scan 1. The sample studied is the stable form A and its
melting endotherm is observed.
Scan 2. The sample studied is the metastable form B
which transforms exothermically in the solid state into the
stable form A. Form A melts at a higher temperature.
Scan 3. The sample studied is the metastable form B,
which does not transform into A but melts
endothermically. From the melt, the stable crystalline form
A is obtained with an exothermic peak and melts at a
higher temperature.
31. Phase Transition of the stable to a metastable form
e.g. Fosinopril Sodium: which exists in at least two enantiotropic.
The stable Form A was found to transform under simulated
granulation conditions. Upon rapid drying from an alcoholic
granulation fluid, the PXRD patterns show conversion to Form
B.
32. Powder X-ray diffraction pattern of fosinopril sodium pure Forms A
(a) and B (b) and after granulation (c) showing conversion to Form
B as predicted.
33. SENYAWA KIMIA
HABIT STRUKTUR INTERNAL
KRISTALIN AMORF
KLATRAT
LAPISAN
SALURAN
NON STOIKIOMETRI
SENYAWA INKLUSI
STOIKIOMETRI
SOLVAT/HIDRAT
POLIMORF
SENYAWA JERATAN
WUJUD TUNGGAL
35. SEM Crystal Habit of (a,c) thin plate-like and (b,d) polyhedral
crystals of paracetamol
36. Infrared (IR), X-ray powder diffraction (XPD) and differential
scanning calorimetry (DSC) studies confirmed that these two
forms of crystals were structurally similar, therefore
polymorphic modifications were ruled out.
Compacts made from thin plate-like crystals exhibited higher
elastic recoveries and elastic energies indicating that these
crystals underwent less plastic deformation during
compression than the polyhedral crystals.
37. PXRD Difractogram of (a) polyhedral and (b) thin plate-like crystals of
paracetamol
a
b
38. Famotidine is a representative third generation of
a histamine H2-receptor antagonist, which is
commonly used to treat stomach and duodenal
ulcers, reflux of stomach acid into the esophagus,
and Zollinger–Ellison syndrome.
Famotidine has two polymorphic forms (A and B)
that differed by the arrangement of intra/
intermolecular hydrogen bonds.
39. Grinding or milling is one of the manufacturing
processes in pharmaceutical industry. Grinding
process can modify the physical and chemical
properties of drugs, such as introduction of a
significant lattice strain within the crystalline drug,
alteration of crystallinity of drug, reduction of particle
size, and induction of polymorphic transformation of
drug polymorphs.
40. Preparation of two crystalline forms of famotidine
Form A: The powder of famotidine was suspended and
dissolved in boiling acetonitrile, then filtrated while hot. The
filtrate was stored in a refrigerator for crystallization. The
crystals collected were dried under vacuum and stored in a
silica gel desiccator.
Form B: The same preparation method of form A, but
acetonitrile was replaced by methanol.
A certain amount of famotidine (form B) was respectively ground
for different times (ranging from 5 to 30 min) in a ceramic mortar.
No decomposition was detected by TLC in the course of grinding
process.
Preparation of ground samples
41. Gambar. Perwakilan FT-IR spektrum dan DSC thermograms dari
bentuk polimorfik A dan B dari famotidine.
42. Gambar. Grinding perubahan tergantung waktu di perwakilan FT-IR spektrum sampel
bentuk famotidine B. Key: bentuk utuh famotidine B sebelum grinding (a), bentuk
famotidine B setelah penggilingan selama 5 menit (b), 10 menit (c), 20 menit (d) dan 30
menit (e), utuh famotidine bentuk A sebelum grinding (f ).
43. Gambar. 4. Pengaruh tingkat pemanasan pada thermograms DSC dua polimorf A dan B
rekristalisasi, serta sampel famotidine tanah yang berbeda. Key: bentuk utuh famotidine B
sebelum grinding (a), bentuk famotidine B setelah penggilingan selama 5 menit (b), 10
menit (c), 20 menit (d) dan 30 menit (e), utuh famotidine bentuk A sebelum grinding (f ). Laju
pemanasan: garis utuh tipis, 1 ◦ C / menit; garis putus-putus, 3 ◦ C / menit; garis utuh tebal,
10 ◦ C / menit.
44. Gambar. The grinding perubahan tergantung waktu di DSC entalpi
fusi untuk campuran tanah famotidine ditentukan dengan 10 ◦ C /
menit.
45. The result of this study demonstrates the polymorphic
transformation of famotidine from form B to form A
might be occurred during grinding process. The
mechanism of this polymorphic transformation of
famotidine seems to be a zero-order kinetic model via
grinding. The grinding process not only decreased the
crystallinity but also reduced the particle size of
famotidine form B, resulting in easy induction of the
polymorphic transformation of famotidine from form B
to form A in the ground famotidine sample.
46. Milling is able to transform ranitidine hydrochloride form 1 to form
2 under a range of temperature conditions.The transformation was
confirmed to occur via an amorphous form. The amorphous drug
was characterized as having a Tg and Tc of 13–30 and 36–65 ◦C,
respectively.
The conversion process was thought to be initiated by the
disruption of orderly form 1 crystal producing form 2 nuclei. With
continued milling, heat generated (in combination with external
temperature) provides the propagation factor for crystallization. It is
believed that both the temperature of the solid and the impact
energy (determined by ball size, quantity and oscillating speed) act
collectively to influence the rate and outcome of milling.
Effect of milling conditions on the solid-state conversion of ranitidine
hydrochloride form 1
47. Gambar. Difraktogram dari bentuk 1 batch yang digiling untuk berbagai kali pada
suhu kamar. Garis putus-putus menunjukkan puncak karakteristik dari bentuk 1;
panah menunjukkan puncak karakteristik dari bentuk 2; Angka inset menunjukkan
halo XRPD dari 150 sampel min giling.
48. Gambar. Thermograms dari bentuk 1 batch yang digiling untuk berbagai kali pada
35 ◦ C (warmroom). Acara transisi kaca ditunjukkan pada sub-grafik diperbesar.
49. Transformation of mefenamic acid polymorphs in
various solvents and under high humidity conditions
Mefenamic acid is a non-steroidal anti-inflammatory drug and
widely used as an antipyretic analgesic and antirheumatic
drug. It has been reported that mefenamic acid has two
polymorphs, forms I and II, and that they showed different
solubility and stability. Form II exhibited higher solubility than
form I in several solvents.
50. The dissolution profile of form II showed
supersaturation accompanying the decrease down
to the solubility of form I due to the transformation
to form I. Conversely, form I transformed to form II
at high temperature (142.5–150 ◦C) and this
transformation followed the zero-order reaction
mechanism (Polany-Winger equation).
51. Gambar. Pola difraksi sinar-X serbuk dan profil DSC bentuk I dan II: (a)
bentuk I; (b) bentuk II.
52. The characteristic XRD peaks of form I were observed at 6.3◦,
21.3◦ and 26.3◦ (2θ), while those of form II were observed at
11.8◦, 17.9◦, 23.8◦ and 25.6◦ (2θ). These results coincided with
those reported previously.
DCS profiles of form I showed two endothermic peaks at 170
and 231 ◦C due to the transformation to form II and the melting
of form II, respectively. Form II exhibited only an endothermic
peak at 233 ◦C due to the melting of form II.
53. Gambar. SEM foto bentuk I dan II: (a) bentuk I; (b) bentuk II. Formulir I
dan II kristal yang partikel berbentuk kubus tongkat-dan, masing-
masing, menunjukkan bahwa mereka cukup berbeda dalam morfologi
partikel mereka.
54. Gambar. 3 Ubah bubuk X-ray pola difraksi bentuk II setelah diskors dalam air
pada 28 ◦ C:. (A) 120 jam; (b) 192 jam; (c) 312 jam; (d) 456 jam. Tertutup dan
terbuka segitiga mewakili puncak karakteristik disebabkan bentuk I and II,
masing-masing.
55. Gambar. Persen sisanya dan SEM foto bentuk II setelah diskors dalam
air, 50% etanol dan etanol: (a) air; (b) 50% etanol; (c) etanol. (0) 28 ◦ C,
(Δ) 33 ◦ C, () 37 ◦ C.
56. Kelarutan obat dalam air, 50% etanol dan etanol pada 40 ◦ C
adalah 0,08 ± 0,01, 23,04 ± 1,22 dan 1.045,2 ± 32,7 mg/100 mL.
Hasil ini didukung bahwa tingkat transformasi tergantung
pada kelarutan asam mefenamat dalam media
menangguhkan.
Oleh karena itu, transformasi bentuk II untuk membentuk aku
dapat dijelaskan sebagai proses di mana bentuk kristal II
sebagian terlarut dalam medium dan kemudian mengkristal
sebagai bentuk stabil I.
