Solid state pharmaceutical

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)

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.

Solid State Bonding 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.

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, trigonal, hexagonal or cubic tetragonal,

7 Sistem Kristal Internal

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.

Acetaminophen can exist as a monoclinic (b) form which is thermodynamically stable under ambient conditions and as a less stable orthorhombic (a) form, has a higher density indicative of closer packing.

On the other hand, the spiperone Molecule contains a flexible CH2-CH2-CH2- chain and is therefore capable of existing in different molecular conformations, give rise to two different conformational polymorphs (denoted Forms I and II), which have different unit cells and densities.

Physical Properties that Differ Among Various Polymorphs

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

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

Amorphous State

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.

amorphous solids consist of disordered arrangements of molecules and therefore possess no distinguishable crystal lattice nor unit cell and consequently have zero crystallinity

Schematic diagram showing the difference in long-range order of silicon dioxide in (a) the crystalline state (crystobalite) and (b) the amorphous state (silica glass).

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

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 80C 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 70C Crystalline form 10% degradation Amorphous form 80% degradation Example 2. Degradation after light exposure, 300 kluxh Crystalline form 2% degradation Amorphous form 38% degradation

A) SEM Amorphous Forms and B) one crystalline form

on the polymorphism of chloramphenicol palmitate followed Andersons 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.

Polimorf Karbamazepine: Bentuk I, II, III dan IV

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.

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.

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.

Unstable Forms

phase transition

Stable Forms

Transition Point 1. TERMODINAMIC : The Changes in various condition function 2. KINETIC : The rate of transformation

Rekristalisasi eksotermik Heat flow Reaksi oksidasi

Suhu pembebasan air hidrat

endotermik

Transisi gelas

Dekomposisi

Transformasi Transformasi polimorfik 1 polimorfik 2

Melebur

larutan
FD SD PR

KR

KR

polimorf sejati

DE,SC,WG

solvat

ME

MI,WG, SDSP KR

KR

DE

DE

ESV

leburan

HE QC

padatan amorf (kaca)

desolvat isomerik

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)

Case of Enantiotropy
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.

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

Tt

TRANSFORMASI POLIMORFIK

ENANTIOTROPI

Tt

T T Tt

MONOTROPI

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.

Melting/crystallization observed under polarized light

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.

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.

SENYAWA KIMIA
HABIT STRUKTUR INTERNAL AMORF

KRISTALIN

WUJUD TUNGGAL

SENYAWA JERATAN

POLIMORF

NON STOIKIOMETRI SENYAWA INKLUSI

STOIKIOMETRI SOLVAT/HIDRAT

SALURAN

LAPISAN

KLATRAT

Vitamin C

Kalsiferol (Vit.D)

Retinol (Vitamin A)

Tokoferol (Vit.E)

Thiamin (Vit.B1)

Riboflavin (Vit.B6)

Asam Folat

Vitamin K2

SEM Crystal Habit of (a,c) thin plate-like and (b,d) polyhedral crystals of paracetamol

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.

PXRD Difractogram of (a) polyhedral and (b) thin plate-like crystals of paracetamol

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 ZollingerEllison syndrome.

Famotidine has two polymorphic forms (A and B) that differed by the arrangement of intra/ intermolecular hydrogen bonds.

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.

Preparation of two crystalline forms of famotidine Form A: The powder of famotidine was suspended dissolved in boiling acetonitrile, then filtrated while hot. filtrate was stored in a refrigerator for crystallization. crystals collected were dried under vacuum and stored silica gel desiccator. and The The in a

Form B: The same preparation method of form A, but acetonitrile was replaced by methanol. Preparation of ground samples 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.

Fig. The representative FT-IR spectra and DSC thermograms of polymorphic forms A and B of famotidine.

Fig. Grinding time-dependent changes in the representative FT-IR spectra of famotidine form B samples. Key: intact famotidine form B before grinding (a), famotidine form B after grinding for 5 min (b), 10 min (c), 20 min (d) and 30 min (e), intact famotidine form A before grinding (f).

Fig. 4. The effect of heating rate on the DSC thermograms of two polymorphs A and B recrystallized, as well as the different famotidine ground samples. Key: intact famotidine form B before grinding (a), famotidine form B after grinding for 5 min (b), 10 min (c), 20 min (d) and 30 min (e), intact famotidine form A before grinding (f). Heating rate: thin solid line, 1 C/min; dotted line, 3 C/min; thick solid line, 10 C/min.

Fig. The grinding time-dependent changes in DSC enthalpy of fusion for the ground famotidine mixture determined with 10 C/min.

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.

Effect of milling conditions on the solid-state conversion of ranitidine hydrochloride form 1

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 1330 and 3665 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.

Fig. Diffractograms of a form 1 batch milled for various times at ambient temperature. Dotted lines show the characteristic peaks of form 1; arrows show characteristic peaks of form 2; figure inset shows the XRPD halo of the 150 min milled sample.

Fig. Thermograms of a form 1 batch milled for various times at 35 C (warmroom). The glass transition event is shown in the enlarged sub-graphs.

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.

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 (142.5150 C) and this transformation followed the zero-order reaction mechanism (Polany-Winger equation).

Fig. Powder X-ray diffraction patterns and DSC profiles of forms I and II: (a) form I; (b) form II.

The characteristic XRD peaks of form I were observed at 6.3, 21.3 and 26.3 (2), while those of form II were observed at 11.8, 17.9, 23.8 and 25.6 (2). 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.

Fig. SEM photographs of forms I and II: (a) form I; (b) form II. Forms I and II crystals were stick- and cube-shaped particles, respectively, indicating that they were quite different in their particle morphology.

Fig. 3. Change of powder X-ray diffraction patterns of form II after being suspended in water at 28 C: (a) 120 h; (b) 192 h; (c) 312 h; (d) 456 h. Closed and open triangles represent the characteristic peaks attributable to forms I and II, respectively.

Fig. Percent remaining and SEM photographs of form II after being suspended in water, 50% ethanol and ethanol: (a) water; (b) 50% ethanol; (c) ethanol. (0) 28 C; () 33C; ( ) 37C.

The solubility of the drug in water, 50% ethanol and ethanol at 40 C were 0.08 0.01, 23.04 1.22 and 1045.2 32.7 mg/100 mL.

These results supported that the transformation rate depended on the solubility of mefenamic acid in the suspending medium. Therefore, the transformation of form II to form I can be explained as the process where form II crystals partially dissolved in the medium and were subsequently crystallized as the stable form I.