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)

Solid state pharmaceutical

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.

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

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 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 spiperoneMolecule 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.

1. Packing propertiesa. Molar volume and densityb. Refractive indexc. Conductivity, electrical and thermald. Hygroscopicity

2. Thermodynamic propertiesa. Melting and sublimation temperaturesb. Internal energy (i.e., Structural energy)c. Enthalpy (i.e., Heat content)d. Heat capacitye. Entropyf. Free energy and chemical potentialg. Thermodynamic activityh. Vapor pressurei. Solubility

Physical Properties that Differ Among Various Polymorphs

3. Spectroscopic propertiesa. 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 propertiesa. Dissolution rateb. Rates of solid state reactionsc. Stability

5. Surface propertiesa. Surface free energyb. Interfacial tensionsc. Habit (i.e., shape)

6. Mechanical propertiesa. Hardnessb. Tensile strengthc. Compactibility, tabletingd. Handling, flow, and blending

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 State

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 80°C under oxygen or moistureCrystalline form A no degradationCrystalline form B 0.5.1.5% degradationAmorphous form 2.3.5% degradation

Example 2. Degradation after 1 week at 70°CCrystalline form 10% degradationAmorphous form 80% degradation

Example 2. Degradation after light exposure, 300 kluxhCrystalline form 2% degradationAmorphous form 38% degradation

A B

A) SEM Amorphous Forms and B) one crystalline form

on the polymorphism of chloramphenicol palmitate followed Anderson’s investigation of the unsatisfactory therapeutic effect of asuspension 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 satisfactoryfor 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 Stable Formsphase transition

Transition Point

1. TERMODINAMIC : The Changes in various condition function

2. KINETIC : The rate of transformation

endo

term

ik

ekso

term

ik

Melebur

Transformasi polimorfik 1

Suhu pembebasan air hidrat

Rekristalisasi

Reaksi oksidasi

Heat

flow

Transformasi polimorfik 2

Transisi gelas Dekomposisi

larutan

polimorf sejati solvat

leburanpadatan amorf

(kaca)desolvat isomerik

KR KRFDSDPR

DE,SC,WG

KR

KR

ME

HE

QC

MI,WG,SDSP

DEDE 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)

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

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 chloramphenicolpalmitate and metolazone

TRANSFORMASI POLIMORFIK

ENANTIOTROPI

MONOTROPI

P

T

TTTt

TtT T

Tt

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

KRISTALIN AMORF

KLATRATLAPISANSALURAN

NON STOIKIOMETRI

SENYAWA INKLUSI

STOIKIOMETRI

SOLVAT/HIDRAT

POLIMORF

SENYAWA JERATANWUJUD TUNGGAL

Kalsiferol (Vit.D)

Tokoferol (Vit.E)

Riboflavin (Vit.B6)

Vitamin K2

Vitamin C

Retinol (Vitamin A)

Thiamin (Vit.B1)

Asam Folat

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

a

b

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.

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 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

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.

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

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 invarious 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 (142.5–150 ◦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◦ (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.

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; (Δ) 33◦C; ( ) 37◦C.

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.